Benzopyrone compounds, their preparation and use

Abstract

The present invention provides a benzopyrone compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a preparation method and use thereof. This type of compound has a good inhibitory effect on POLRMT and can be used to treat and / or prevent diseases mediated by POLRMT, such as cancer. JPEG2025538893000280.jpg28166

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority from two Chinese applications, one filed on December 1, 2022 with application number 202211527029.6, and the other filed on February 6, 2023 with application number 202310065010.2, both of which are incorporated herein in their entireties.

[0002] (Technical field) The present invention relates to the technical field of medicinal chemistry, specifically, for example, benzopyrone compounds, their preparation methods and their uses. [Background technology]

[0003] Cancer is a disease caused by the abnormal proliferation of cells. Cancer cells not only divide uncontrollably, but also locally invade surrounding normal tissues or metastasize to other parts of the body via the circulatory or lymphatic systems, causing damage or even death. Cancer is characterized by a high mortality rate, poor prognosis, and high treatment costs. Cancer patients generally endure significant physical pain, making it a pressing medical and health issue. Despite decades of research, technological innovation, and drug development, traditional cancer treatments, such as chemotherapy, radiation therapy, and immunotherapy, still fail to meet current cancer treatment needs and face challenges such as serious side effects and drug resistance. Therefore, improved and alternative treatments are still needed to combat cancer in the foreseeable future.

[0004] Interfering with cancer metabolism is another principle of cancer treatment. Reprogramming of energy metabolism, which promotes rapid cell growth and proliferation by regulating energy metabolism, is considered a hallmark of malignant tumors. Therefore, targeting metabolic reprogramming is an important direction in the development of oncology drugs (Luengo et al., 2017, Cell Chem Biol 24, 1161-1180). Since the discovery of the so-called Warburg effect, which suggests that the much faster growth rate of cancer cells than normal cells is due to differences in the energy source—that is, the use of glycolysis over mitochondrial oxidative phosphorylation in normal cells—it has been hypothesized that oxidative phosphorylation (OXPHOS) is generally downregulated in cancer. Research has focused on pharmacological inhibition of glycolysis. However, many glycolysis inhibitors (e.g., 2-deoxyglucose) do not have the expected clear effect on tumor growth. While this is certainly true in many cancers, this hypothesis is increasingly being questioned in some cancers. A growing body of evidence supports intact mitochondrial metabolism in leukemia, lymphoma, pancreatic ductal adenocarcinoma, high-OXPHOS melanoma, and endometrial cancer (Luengo et al., 2017, Cell Chem Biol 24, 1161-1180; Moreno-Sanchez et al., 2007, FEBS J 274, 1393-1418).Recent studies have provided compelling evidence supporting the heterogeneity of tumor metabolism, suggesting that in some tumors, oxidative phosphorylation (OXPHOS) provides energy (Hu et al., 2013, Nat Biotechnol 31, 522-529; Roesch et al., 2013, Cancer Cell 23, 811-825; Sriskanthadevan et al., 2015, Blood 125, 2120-2130). Increased OXPHOS levels, increased mitochondrial contribution to cellular energy, increased carbon from fatty acids and glucose entering the tricarboxylic acid (TCA) cycle, and increased lipogenesis are crucial for promoting tumor growth (Birsoy et al., 2015, Cell 162, 540-551; Martinez-Reyes et al., 2020, Nature 585, 288-292; Sullivan et al., 2015, Blood 125, 2120-2130). al., 2015, Cell 162, 552-563), suggesting that targeting OXPHOS may lead to effective cancer treatment strategies.

[0005] Studies have demonstrated that acquired therapeutic resistance shifts tumor cells from using glycolysis to using OXPHOS. This metabolic heterogeneity allows tumors to adapt to changing environments and survive. For example, inhibition of OXPHOS can overcome resistance to chemotherapy (Cannavino et al., 2014, J Physiol 592, 4575-4589; Farge et al., 2017, Cancer Discov 7, 716-735; Lee et al., 2017, Cell Metab 26, 633-647 e637) and tyrosine kinase inhibitors (Zhang et al., 2019, Sci Transl Med 11). OXPHOS is upregulated in some gene mutation subtypes, such as RB1-deficient, SMARCA4-mutated, and PTEN-mutated tumors (Ashton et al., 2018, Clin Cancer Res 24, 2482-2490). This is also true for high-OXPHOS tumor subtypes such as high-OXPHOS diffuse large B-cell lymphoma (Caro et al., 2012, Cancer Cell 22, 547-560). Currently, tumor types reported to exhibit elevated oxidative phosphorylation include acute lymphoblastic leukemia (ALL), colorectal cancer (CRC), glioma, diffuse large B-cell lymphoma, endometrial cancer, esophageal squamous cell carcinoma (ESCC), head and neck cancer, non-Hodgkin lymphoma, ovarian cancer, papillary thyroid cancer, prostate cancer, and salivary gland eosinophilic adenoma (Ashton et al., 2018, Clin Cancer Res 24, 2482-2490; Xu et al., 2020, J Med Chem 63, 14276-14307).

[0006] These evidences suggest novel uses for OXPHOS inhibitors, namely, for the treatment of cancers in which OXPHOS is upregulated or for improving therapeutic efficacy by alleviating tumor hypoxia. Alleviating tumor hypoxia can be achieved in cancers in which OXPHOS is not upregulated, and such inhibitors can be widely used. Cancer-related research has also reported targeted inhibitors of respiratory chain complexes I–V, mitochondrial ribosomes, inhibitors controlling translation of respiratory chain subunits, and related enzyme inhibitors (Ashton et al., 2018, Clin Cancer Res 24, 2482–2490; Xu et al., 2020, J Med Chem 63, 14276–14307).

[0007] Recently, mitochondrial RNA polymerase (POLRMT, also known as mtRNAP) has attracted attention as a novel target for tumor metabolism as a regulatory gene controlling the OXPHOS process. For example, inhibiting POLRMT can inhibit AML tumor growth, a finding confirmed in the mouse CDX model, and POLRMT gene upregulation is positively correlated with poor prognosis in AML (Bralha et al., 2015, Oncotarget 6, 37216-37228). POLRMT regulates mitochondrial gene expression and initiates mitochondrial genome replication by providing an RNA primer, which in turn initiates transcription of the 13 subunits of the OXPHOS complex (complexes I, III, and IV), serving as an RNA primer for mitochondrial DNA replication. Inhibiting POLRMT affects mtDNA transcription, resulting in reduced mtDNA expression and reduced OXPHOS levels.

[0008] Therefore, developing drugs that specifically inhibit POLRMT has important implications for cancer research. Summary of the Invention [Problem to be solved by the invention]

[0009] The technical problem that the present invention aims to solve is how to develop drugs that specifically inhibit POLRMT to effectively treat and intervene in cancer. [Means for solving the problem]

[0010] Specifically, the present invention provides the following technical solutions to solve the above technical problems.

[0011] A benzopyrone compound represented by formula (I), or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated product thereof, or a hydrate thereof, or a solvate thereof, [ka] wherein X1 and X2 are each independently selected from O or an NH group; Y is selected from a CR group or N; wherein R is H or a C1-C3 alkyl group; R1 and R1' may be the same or different and are each independently selected from hydrogen, an alkyl group, a cycloalkyl group, an aryl group, a heterocyclyl group, or a heteroaryl group; L1 and L3 are each independently selected from -O-, -S-, -NR3-, -CR2R3-, -CR2(R3), -CO-, -SO- or -SO2- groups; L2 is a direct bond, -CR2R3-, -CR2(R3)- or -C(R2R3)-, where R2 is selected from H or a C1-C4 chain alkyl group, and R3 is selected from H or a C1-C4 chain alkyl group, or R2 and R3 in one pair of -CR2(R3) together form one oxyylidene; R4, R5 and R6 are H, halogen, -C-OR8(R9), -CR8(R9), -CN, -NO2, -OR8, -NR8R9, -SR8, -COR8, -SOR8, -S02R8, -NR8COR9, -CONR8R9, -OCOR8, -COOR8, -OCONR8R9, -NR8CONR9R, respectively. 10, -NR8COOR9, -NR8SO2R9, -SO2NR8R9, -OSO2R8, -SO3R8, a chain alkyl group, a heterochain alkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkene group, an alkyne group, an aryl group or a heteroaryl group, or an aromatic fused heterocyclyl group, wherein R8, R9, R 10 are each independently selected from H, a linear alkyl group, a heterocyclic alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, wherein the linear alkyl group, the heterocyclic alkyl group, the cycloalkyl group, the heterocycloalkyl group, the aryl group, or the heteroaryl group is independently selected from one or more R 11 and R 11 is selected from halogen, cyano, hydroxy, mercapto, ether, nitro, alkoxy, amino, amine, carboxy, sulfonic acid, ester, acyloxy, amide, sulfonate ester, sulfonamide, linear alkyl, heterocyclic alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or aromatic fused heterocyclyl, wherein each linear alkyl, heterocyclic alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or aromatic fused heterocyclyl group is independently substituted by one or more halogen, cyano, hydroxy, mercapto, ether, nitro, alkoxy, amino, amine, carboxy, sulfonic acid, ester, amide, sulfonate ester, sulfonamide, alkyl, or haloalkyl group; or R4 and R5 together form an oxyylidene; Or, any two or three of R4, R5 and R6, together with the carbon atom bonded to L3, form a cyclic group A bonded to L3. [ka] wherein the cyclic group A is an arylcyclyl group, a saturated or unsaturated cycloalkyl group, a monoheterocyclyl group, a fused heterocyclyl group, a benzoheterocyclyl group, a spirocyclic group, a bridged ring group, and the like, and ... 11 any one cyclic group is selected from cyclic groups substituted by W is hydrogen, H, alkyl group, -CR 8a R 9a R 10a , -NR 8a R 9a , -OR 10a or a cyclic group B1 containing a carbon atom and attached to the benzopyrone ring by said carbon atom, substituted by one or more R7. [ka] or a cyclic group B2 containing a nitrogen atom and bonded to the benzopyrone ring by the nitrogen atom [ka] where R 8a , R 9a and R 10a are each independently selected from H, halogen, alkyl groups, cyano groups, hydroxy groups, mercapto groups, ether groups, nitro groups, alkoxy groups, amino groups, amine groups, carboxy groups, sulfonic acid groups, ester groups, acyloxy groups, amide groups, sulfonate ester groups, sulfonamide groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, and aromatic fused heterocyclyl groups, and the cyclic group B1 and cyclic group B2 are each independently selected from cycloalkyl groups, heterocycloalkyl groups, aryl groups, and heteroaryl groups.

[0012] Here, R7 is H, halogen, -CN, -NO2, -OR8, -NR8R9, -SR8, -COR8, -SOR8, -SOR8, -NR8COR9, -CONR8R9, -OCOR8, -COOR8, -OCONR8R9, -NR8CONR9R 10, -NR8COOR9, -NR8SO2R9, -SO2NR8R9, -OSO2R8, -SO3R8, a chain alkyl group, a heterochain alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl or heteroaryl group, or an aromatic fused heterocyclyl group, preferably selected from a halogen, an alkyl group, a cyano group, a hydroxy group, a mercapto group, an ether group, a nitro group, an alkoxy group, an amino group, an amine group, a carboxy group, a sulfonic acid group, an ester group, an amide group, an acyloxy group, a sulfonate ester group, a sulfonamide group, a cycloalkyl group, a heterocycloalkyl group, an aryl or heteroaryl group, and wherein each chain alkyl group, heterochain alkyl group, cycloalkyl group, heterocycloalkyl group, aryl or heteroaryl group, or aromatic fused heterocyclyl group is independently selected from one or more R 11 and R, R and R 10 The meaning of R8, R9 and R 10 is exactly the same as the meaning of However, formula (I) does not include the following compounds: [ka]

[0013] In one embodiment, in the above-mentioned compound of the present invention, or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated product thereof, or a hydrate thereof, or a solvate thereof, X1 is an -O- group, X2 is an -O- group, Y is a -CR- group, and R1 and R1' are both hydrogen; or X1 is a -NH- group, X2 is a -O- group, Y is a -CR- group, and R1 and R1' are both hydrogen; or X1 is an -O- group, X2 is an -NH- group, Y is a -CR- group, and R1 and R1' are both hydrogen; Or, X1 is an -O- group, X2 is an -O- group, Y is an -N- group, and R1 and R1' are both hydrogen.

[0014] In one embodiment, in the above-mentioned compound of the present invention, or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated product thereof, or a hydrate thereof, or a solvate thereof, -L1-L2-L3- as a whole is any one group selected from the group consisting of -O-CR2(R3)-CO-, -O-CR2R3-CO-, -CR2(R3)-CR2(R3)-CO-, -NR3-CR2(R3)-CO-, -S-CR2(R3)-CO-, -SO2-CR2(R3)-CO-, -O-CR2(R3)-CR2R3-, -O-CR2(R3)-SO2- and -CR2(R3)-NR3-CO-; Here, R2 is preferably one of H, a methyl group, and an ethyl group, more preferably a methyl group, and R3 is preferably a methyl group or H, more preferably H.

[0015] In one embodiment, in the compound of any one of the above-mentioned invention, or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated product thereof, or a hydrate thereof, or a solvate thereof, -L1-L2-L3- as a whole is any one group selected from the group consisting of -O-CH(CH3)-CO-, -O-CR2(R3)-CO-, -CR2R3-CH(CH3)-CO-, -NR3-CH(CH3)-CO-, -S-CH(CH3)-CO-, -SO2-CH(CH3)-CO-, -O-CR2(R3)-CR2(R3)-, -O-CH(CH3)-SO2-, or -CR2(R3)-NR3-CO-.

[0016] In one embodiment, in the compound according to any one of the above aspects of the present invention, or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated product thereof, or a hydrate thereof, or a solvate thereof, the cyclic group A is a C3 to C 12 Cycloalkyl groups, C3-C 12 Heterocycloalkyl groups, C5-C 12 Aryl groups and C5-C 12 Any one cyclic group is selected from heteroaryl groups, preferably C3 to C 12selected from a cycloalkyl group, a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group, an anthraquinone group, a furyl group, a pyrrolyl group, a thienyl group, a pyrazolyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, an isothiazolyl group, a pyridyl group, a pyranyl group, a thiopyranyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a piperazinyl group, an indolyl group, a benzimidazolyl group, a carbazolyl group, a thiazolinyl group, a quinolinyl group, an isoquinolinyl group, a purinyl group, an acridinyl group, a phenazinyl group, and a phenothiazinyl group; More preferably, the cyclic group A is any one selected from the following cyclic groups: [ka] Here, these cyclic groups A may be substituted with one or more groups selected from a halogen, a cyano group, a hydroxy group, a mercapto group, an ether group, a nitro group, an alkoxy group, an amino group, an amine group, a carboxy group, a sulfonic acid group, an ester group, an amide group, a sulfonate ester group, a sulfonamide group, a linear alkyl group, a heterolinear linear alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, and a heteroaryl group.

[0017] In one embodiment, in the compound according to any one of the above claims of the present invention, or its stereoisomer, or its salt, or its prodrug, or its deuterated product, or its hydrate, or its solvate, R4, R5, and R6 are each independently selected from -CR8(R9), where R8 is H, a chain alkyl group, a cyano group, or a cycloalkyl group, and when R9 is a chain alkyl group, a heterochain alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group substituted with a halogen, a cyano group, a hydroxy group, a mercapto group, an ether group, a nitro group, an alkoxy group, an amino group, an amine group, a carboxy group, a sulfonic acid group, an ester group, an acyl group, an amide group, a sulfonic acid ester group, or a sulfonamide group, R9 is bonded to the carbon atom bonded to L3 by an oxygen atom, a nitrogen atom, or a carbon atom on the substituent.

[0018] In one embodiment, in the compound of the present invention described in any one of the above, or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated product thereof, or a hydrate thereof, or a solvate thereof, the substituted cyclic group B1 and the substituted cyclic group B2 are each independently selected from a halocycloalkyl group, a haloheterocycloalkyl group, a haloaryl group, and a haloheteroaryl group; More preferably, the substituted cyclic group B1 and the substituted cyclic group B2 are each independently a 2-chloro-4-fluorophenyl group, a chlorophenyl group, a methyl-substituted phenyl group, an amido-substituted phenyl group, an amino-substituted phenyl group, or a phenylalkyl group.

[0019] In one embodiment, in the compound according to any one of the above aspects of the present invention, or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated product thereof, or a hydrate thereof, or a solvate thereof, the cyclic group B1 is a C5-C 10 Aryl groups, C5-C 10 Heteroaryl groups, C3-C 10 Cycloalkyl group or C3-C 10 It is a heterocycloalkyl group.

[0020] In one embodiment, in the compound according to any one of the above aspects of the present invention, or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated product thereof, or a hydrate thereof, or a solvate thereof, the compound of formula (I) is selected from compounds represented by any one of the following structural formulas: [ka] In the formula, R7 is preferably F, Cl, Br, I, OH, OR2, C 1~3 R1 and R1' are one or more of an alkyl group, a sulfonic acid group, a nitro group, an amino group, and an amine group, and R1 and R1' are hydrogen, C 1~4 Alkyl group, C 1~4 alkoxy groups, wherein R2 is as defined in claim 1, and n is an integer of 0 to 5; [ka] In the formula, R7 is preferably F, Cl, Br, I, OH, OR 2a , C 1~3 R is one or more of an alkyl group, a sulfonic acid group, a nitro group, an amino group, or an amine group. 11 is preferably F, Cl, Br, I, C 1~4 Alkoxy group, acyl group, or C 1~3 Alkyl group, sulfonic acid group, nitro group, amino group, cyano group, amine group, -C 0~4 Alkyl-COOH, ester group, acyloxy group, ether group, amide group, amine acyl group, cycloalkyl-substituted amine acyl group, aralkyl-substituted amine acyl group, carboxy-substituted C 1~3 Alkoxy group, carboxy-substituted amine group, cycloalkyl-substituted C 1~3 C containing alkoxy and acyloxy groups 3~5 a cycloalkyl group, or [ka] wherein R 11 may form a benzene-fused nitrogen heterocyclic or oxygen heterocyclic structure with the benzene ring bonded thereto, and R and R′ are hydrogen, C 1~4 Alkyl group, C 1~4 alkyloxy groups, R 2a is selected from a C1-C4 alkyl group, a C1-C4 alkenyl group, a C1-C2 alkoxy-substituted C1-C4 alkyl group, and a C1-C4 alkyl-substituted formyl group, and n is an integer of 0 to 5; [ka] In the formula, R 11 is preferably -C 0~4 alkyl-COOH, and R and R are hydrogen, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 1~4independently selected from alkylphenyl groups; [ka] During the ceremony, [ka] is preferably C 1~4 Alkyl group, C 1~4 is an alkylphenyl group, more preferably a methyl group, an isobutyl group, or a benzyl group; R 11 is preferably -C 0~4 alkyl-COOH, and R and R are hydrogen, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 1~4 independently selected from alkylphenyl groups; [ka] In the formula, R 10 is preferably C 1~4 Alkyl, hydroxy-substituted C 1~4 Alkyl group, C 1~4 Alkoxy or hydroxy substituted C 1~4 is an alkoxy group, and R 11 is preferably —C0-C4 alkyl-COOH, and R1 and R1′ are hydrogen, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 1~4 independently selected from alkylphenyl groups; [ka] In the formula, R8 and R9 are hydrogen or C 1~4 independently selected from alkyl groups, R 11 is preferably —C0-C4 alkyl-COOH, and R1 and R1′ are hydrogen, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 1~4 independently selected from alkylphenyl groups; [ka] In the formula, the cyclic group B1 is preferably C 3~12 a cycloalkyl group, a 4- to 10-membered heterocyclyl group, or a 5- to 10-membered aryl group; R 11 is preferably —C0-C4 alkyl-COOH, and the heterocyclyl group is more preferably any one of a furyl group, a pyrrolyl group, a thienyl group, a pyrazolyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, an isothiazolyl group, a pyridyl group, a pyranyl group, a thiopyranyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a piperazinyl group, an indolyl group, a benzimidazolyl group, a carbazolyl group, a thiazolinyl group, a quinolinyl group, an isoquinolinyl group, a purinyl group, an acridinyl group, a phenazinyl group, and a phenothiazinyl group, and both R1 and R1′ are preferably hydrogen, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 1~4 The cyclic group B1 is an alkylphenyl group, and the cyclic group B1 may optionally contain one or more hydrogen, halogen, hydroxyl, C 1~6 Alkyl group, C 1~6 substituted or unsubstituted with hydroxy groups, amino groups, amine groups substituted with alkyl groups, [ka] In the formula, the cyclic group B2 is preferably C 3~12 a cycloalkyl group, a 4- to 10-membered heterocyclyl group, or a 5- to 10-membered aryl group; R 11 is preferably -C 0~4The heterocyclyl group is more preferably any one of a furyl group, a pyrrolyl group, a thienyl group, a pyrazolyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, an isothiazolyl group, a pyridyl group, a pyranyl group, a thiopyranyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a piperazinyl group, an indolyl group, a benzimidazolyl group, a carbazolyl group, a thiazolinyl group, a quinolinyl group, an isoquinolinyl group, a purinyl group, an acridinyl group, a phenazinyl group, and a phenothiazinyl group; R and R are both preferably hydrogen; the cyclic group B is hydrogen, a halogen, a hydroxy group, C 1~6 Alkyl group, C 1~6 substituted or unsubstituted with one or more groups arbitrarily selected from hydroxy groups, amino groups, and amine groups substituted with alkyl groups; [ka] In the formula, R7 is preferably F, Cl, Br, I, OH, OR 2a , C 1~6 R is any one or more of an alkyl group, a sulfonic acid group, a nitro group, an amino group, and an amine group, and more preferably, chlorine and fluorine simultaneously substitute the benzene ring in the structural formula, and R 11 is preferably F, Cl, Br, I, oxo, C 1~3 Alkoxy group or alkyl group, cycloalkyl group, sulfonic acid group, nitro group, amino group, cyano group, amine group, -C 0~4 R1 and R1' are any one or more of an alkyl-carboxy group, an ester group, an acyloxy group, and an ether group, and R1 and R1' are hydrogen, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 1~4 alkylphenyl groups, n is an integer from 0 to 5, and R 2a is selected from a C1-C4 alkyl group, a C1-C4 alkenyl group, a C1-C2 alkoxy-substituted C1-C4 alkyl group, and a C1-C4 alkyl-substituted formyl group; [ka] The R7 is preferably F, Cl, Br, I, OH, OR 2a , C 1~6 R is any one or more of an alkyl group, a sulfonic acid group, a nitro group, an amino group, and an amine group, and more preferably, chlorine and fluorine simultaneously substitute the benzene ring in the structural formula, and R 11 is preferably F, Cl, Br, I, oxo, C 1~6 Alkoxy group, C 1~6 Alkyl group, cycloalkyl group, sulfonic acid group, nitro group, amino group, cyano group, amine group or -C 0~4 alkyl-carboxy groups, and R1 and R1' are hydrogen, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 1~4 alkylphenyl groups, n is an integer from 0 to 5, and R 2a is selected from a C1-C4 alkyl group, a C1-C4 alkenyl group, a C1-C2 alkoxy-substituted C1-C4 alkyl group, and a C1-C4 alkyl-substituted formyl group; [ka] In the formula, R7 is preferably F, Cl, Br, I, OH, OR 2a , C 1~6 R is any one or more of an alkyl group, a sulfonic acid group, a nitro group, an amino group, and an amine group, and more preferably, chlorine and fluorine simultaneously substitute the benzene ring in the structural formula, and R 11 is preferably F, Cl, Br, I, oxo, C 1~6 Alkoxy group, C 1~6 Alkyl group, C 3~10 Cycloalkyl group, sulfonic acid group, hydroxy group, hydroxy-substituted C 1~6 Alkyl group, nitro group, amino group, cyano group, amine group or -C 0~4 alkylcarboxy groups, n is an integer of 0 to 5, and R 2ais selected from a C1-C4 alkyl group, a C1-C4 alkenyl group, a C1-C2 alkoxy-substituted C1-C4 alkyl group, and a C1-C4 alkyl-substituted formyl group; [ka] In the formula, R7 is preferably F, Cl, Br, I, OH, OR 2a , C 1~6 Alkyl group, C 3~10 R is any one or more of a cycloalkyl group, a sulfonic acid group, a nitro group, an amino group, and an amine group, and more preferably, chlorine and fluorine simultaneously substitute the benzene ring in the structural formula, and R 11 is preferably F, Cl, Br, I, oxo, C 1~3 Alkoxy group or alkyl group, cycloalkyl group, sulfonic acid group, hydroxy group, nitro group, amino group, cyano group, amine group, -C 0~4 alkylcarboxy groups, n is an integer of 0 to 5, and R 2a is selected from a C1-C4 alkyl group, a C1-C4 alkenyl group, a C1-C2 alkoxy-substituted C1-C4 alkyl group, and a C1-C4 alkyl-substituted formyl group; [ka] In the formula, R7 is preferably F, Cl, Br, I, OH, OR 2a or C 1~3 R is any one or more of an alkyl group, a sulfonic acid group, a nitro group, an amino group, and an amine group, and more preferably, chlorine and fluorine simultaneously substitute the benzene ring in the structural formula, and R 11 may be hydrogen, F, Cl, Br, I, oxo, C 1~6 Alkoxy group, C 1~6 Alkyl group, C 3~10 Cycloalkyl group, sulfonic acid group, hydroxy group, nitro group, amino group, cyano group, amine group, -C 0~4 alkylcarboxy groups, n is an integer of 0 to 5, and R2a is selected from a C1-C4 alkyl group, a C1-C4 alkenyl group, a C1-C2 alkoxy-substituted C1-C4 alkyl group, and a C1-C4 alkyl-substituted formyl group; [ka] In the formula, the cyclic group A is a halogen, a cyano group, a hydroxy group, a mercapto group, an ether group, a nitro group, an alkoxy group, an amino group, an amine group, -C 0~4 an aryl group, a cycloalkyl group, a heterocycloalkyl group, or a heteroaryl group, which may or may not be substituted with one or more groups selected from an alkyl-carboxy group, a sulfonic acid group, an ester group, an amide group, a sulfonate ester group, a sulfonamide group, a chain alkyl group, a heterochain alkyl group, a cycloalkyl group, and a heterocycloalkyl group, wherein the cycloalkyl group is preferably C 3~6 The heterocycloalkyl group is preferably any one of an oxiranyl group, an oxetanyl group, an aziridinyl group, an azetidinyl group, and a thietanyl group, and the heteroaryl group is preferably a furyl group, a thienyl group, a pyrrolyl group, an oxazolyl group, a thiazolyl group, an imidazolyl group, a pyrazolyl group, a 5-membered heteroaryl group such as an oxygen-containing imidazolyl group or a pyrazolyl group, a pyridyl group, a pyrimidinyl group, a pyranyl group, a pyridazinyl group, a pyrazidin ... and heterocyclic-fused heterocyclyl groups such as benzofuryl, benzothienyl, benzopyrrolyl, indolyl, quinolinyl, isoquinolinyl, benzopyranyl, benzo-γ-pyrone-formed benzoheterocyclyl groups, and purinyl groups, W is preferably a 2-chloro-4-fluoro-substituted phenyl group or a 2-methylphenyl group, R and R are each independently hydrogen, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 1~4 independently selected from alkylphenyl groups; [ka] In the formula, the cyclic group A is preferably a fused ring or aromatic fused heterocyclyl group, more preferably a benzoheterocyclyl group such as a benzofuryl group, a benzothienyl group, a benzopyrrolyl group, an indolyl group, a quinolinyl group, an isoquinolinyl group, a benzopyranyl group, or a group formed by benzo-γ-pyrone, W is preferably a 2-chloro-4-fluoro-substituted phenyl group or a 2-methylphenyl group, R1 and R1′ are each hydrogen, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 1~4 independently selected from alkylphenyl groups; [ka] wherein the cyclic group A is preferably selected from spirocyclic or bridged ring groups, W is preferably a 2-chloro-4-fluorosubstituted benzene or 2-methylphenyl group, R1 and R1′ are hydrogen, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 1~4 independently selected from alkylphenyl groups; [ka] In the formula, the cyclic group A is preferably a phenyl group, a halophenyl group, -C 0~4 is preferably a 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl group; R and R′ are each independently hydrogen, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 1~4 independently selected from alkylphenyl groups; [ka] wherein the cyclic group A is preferably R 11 as F, Cl, Br, I, oxo, C 1~6Alkoxy group, C 1~6 Alkyl group, C 3~10 Cycloalkyl group, sulfonic acid group, nitro group, amino group, cyano group, amine group or -C 0~4 The cyclic group A is preferably a phenyl group substituted or unsubstituted by one or more of the alkyl-carboxy groups, and further preferably R 11 W is preferably a 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl group, R and R are hydrogen, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 1~4 independently selected from alkylphenyl groups; [ka] wherein the cyclic group A is preferably R 11 as F, Cl, Br, I, oxo, C 1~6 Alkoxy group, C 1~6 Alkyl group, C 3~10 Cycloalkyl group, sulfonic acid group, nitro group, amino group, cyano group, amine group or -C 0~4 The cyclic group A is preferably a phenyl group substituted or unsubstituted by one or more of the alkyl-carboxy groups, and further preferably R 11 W is preferably a 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl group, R and R are hydrogen, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 1~4 independently selected from alkylphenyl groups; [ka] wherein the cyclic group A is preferably R 11 as F, Cl, Br, I, oxo, C 1~6 Alkoxy group, C 1~6 Alkyl group, C 3~10Cycloalkyl group, sulfonic acid group, nitro group, amino group, cyano group, amine group or -C 0~4 The cyclic group A is preferably a phenyl group substituted or unsubstituted by one or more of the alkyl-carboxy groups, and further preferably R 11 W is preferably a 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl group, R and R are hydrogen, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 1~4 independently selected from alkylphenyl groups; [ka] wherein the cyclic group A is preferably R 11 as F, Cl, Br, I, oxo, C 1~6 Alkoxy group, C 1~6 Alkyl group, C 3~10 Cycloalkyl group, sulfonic acid group, nitro group, amino group, cyano group, amine group or -C 0~4 The cyclic group A is preferably a phenyl group substituted or unsubstituted by one or more of the following groups: R 11 W is preferably a 2-chloro-4-fluoro-substituted benzene, R and R are hydrogen, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 1~4 independently selected from alkylphenyl groups; [ka] In the formula, R7 is hydrogen, C 1~4 Alkyl group, C 1~4 alkoxy groups, n is an integer of 0 to 5, R2 and R3 are each selected from hydrogen, C 1~4 R4 and R5 are independently selected from alkyl groups, and R4 and R5 together form an oxyylidene; [ka] In the formula, R2 and R3 are each independently preferably hydrogen, C 1~6 or one pair of R2 and R3 together form an oxyylidene, and another pair of R2 and R3 are independently preferably hydrogen, C 1~6 is an alkyl group, and R and R′ are hydrogen, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 1~4 independently selected from alkylphenyl groups; [ka] wherein the cyclic group A is preferably F, Cl, Br, I, oxo, C 1~6 Alkoxy group, C 1~6 Alkyl group, C 3~10 is a phenyl group which may be unsubstituted or substituted with one or more of a cycloalkyl group, a sulfonic acid group, a nitro group, an amino group, a cyano group, an amine group, or a carboxy group, and the cyclic group A is preferably R as a carboxy group. 11 W is preferably a 2-chloro-4-fluorosubstituted benzene or 2-methylphenyl group, and R and R are both preferably hydrogen; [ka] wherein the cyclic group A is preferably R 11 as F, Cl, Br, I, oxo, C 1~6 Alkoxy group, C 1~6 Alkyl group, C 3~10 Cycloalkyl group, sulfonic acid group, nitro group, amino group, cyano group, amine group or C 0~4 The cyclic group A is preferably a phenyl group substituted by one or more of the following groups: R 11W is preferably a 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl group, R and R are hydrogen, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 1~4 independently selected from alkylphenyl groups; [ka] The cyclic group A is preferably F, Cl, Br, I, oxo, C 1~6 Alkoxy group, C 1~6 Alkyl group, C 3~10 Cycloalkyl group, sulfonic acid group, nitro group, amino group, cyano group, amine group or C 0~4 The cyclic group A is preferably a phenyl group substituted or unsubstituted by one or more of the following groups: R 11 W is preferably a 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl group, R and R are hydrogen, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 1~4 independently selected from alkylphenyl groups; [ka] wherein the cyclic group A is preferably F, Cl, Br, I, oxo, C 1~6 Alkoxy group, C 1~6 Alkyl group, C 3~10 Cycloalkyl group, sulfonic acid group, nitro group, amino group, cyano group, amine group or C 0~4 The cyclic group A is preferably a phenyl group substituted by one or more of the following groups: R 11 W is preferably a 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl group, R and R are hydrogen, C 1~4 Alkyl group, C1~4 Alkoxy group, C 1~4 independently selected from alkylphenyl groups; and [ka] wherein the cyclic group A is preferably F, Cl, Br, I, oxo, C 1~6 Alkoxy group, C 1~6 Alkyl group, C 3~10 Cycloalkyl group, sulfonic acid group, nitro group, amino group, cyano group, amine group or C 0~4 The cyclic group A is preferably a phenyl group substituted by one or more of the following groups: R 11 W is preferably a 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl group, R and R are hydrogen, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 1~4 alkylphenyl groups.

[0021] The present invention also provides a pharmaceutical composition comprising any one of the compounds described above, or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated form thereof, or a hydrate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0022] The present invention also provides use of any one of the compounds described above, or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated form thereof, or a hydrate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above, in the manufacture of a medicament for use as a POLRMT inhibitor.

[0023] The present invention also provides use of any one of the compounds described above, or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated product thereof, or a hydrate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above, in the manufacture of a drug for use in treating a disease associated with abnormally high expression of POLRMT due to oxidative phosphorylation.

[0024] In a more specific embodiment, the use according to the invention is characterized in that said disease is cancer, preferably said cancer is melanoma, metastatic melanoma, pancreatic cancer, pancreatic ductal adenocarcinoma, prostate cancer, lung cancer, hepatocellular carcinoma, lymphoma, leukemia, multiple myeloma, breast cancer, glioma, glioblastoma, cervical cancer, renal cancer, colorectal cancer or ovarian cancer. [Effects of the Invention]

[0025] The beneficial technical effects obtained by the present invention are as follows: 1) The compounds of the present invention have better inhibitory activity against ovarian cancer cells than the compounds disclosed in the prior art.

[0026] 2) The compounds of the present invention have good pharmacokinetic properties, such as good parameters such as Cmax and AUC. [Brief explanation of the drawings]

[0027] [Figure 1] FIG. 10 shows the results of BLI imaging of the MOLM-13-luc orthotopic mouse tumor model in Experimental Example 4. [Figure 2] FIG. 10 is a survival curve diagram of the MOLM-13-luc orthotopic mouse tumor model of Experimental Example 4. DETAILED DESCRIPTION OF THE INVENTION

[0028] The present invention provides the following three technical solutions to develop drugs that specifically inhibit POLRMT and effectively treat, prevent, or inhibit cancer:

[0029] (First technical solution) One object of the present invention is to provide benzopyrone compounds represented by general formula α-(I), general formula α-(II), general formula α-(III), etc., and pharmaceutically acceptable salts thereof. Another object of the present invention is to provide a pharmaceutical composition comprising any of the above compounds, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Another object of the present invention is to provide a use of a compound of the above general formula or a pharmaceutically acceptable salt thereof as a POLRMT inhibitor or in the manufacture of a medicament for a disease associated with abnormally high expression of POLRMT due to oxidative phosphorylation. Another object of the present invention is to provide the use of a compound of the above general formula or a pharmaceutically acceptable salt thereof in a medicament for treating and / or preventing cancer, such as melanoma, metastatic melanoma, pancreatic cancer, pancreatic ductal adenocarcinoma, prostate cancer, lung cancer, hepatocellular carcinoma, lymphoma, leukemia, myeloma, breast cancer, glioma, glioblastoma, cervical cancer, renal cancer, colorectal cancer or ovarian cancer. Another object of the present invention is to provide a method for preparing compounds of the above general formula.

[0030] To achieve the above objectives, the technical solutions adopted by the present invention are as follows: In some embodiments of the present invention, there is provided a compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof: [ka] In the formula, R1, R2, and R3 are independently selected from a hydrogen atom and a C1-C6 alkyl group, and R1, R2, and R3 are not simultaneously hydrogen atoms, Or, R1 and R2 are bonded to each other to form a ring as shown below, and R3 is a hydrogen atom or is absent, [ka] optionally, the ring formed by bonding R1 and R2 together is substituted with m R'; m is selected from 0, 1, 2, 3, 4 or 5; R' is a hydrogen atom, an amino group, a carboxy group, or C 1~6 alkylcarboxy groups, R4 and R5 are hydrogen atoms, halogens, C 1~6 independently selected from alkyl groups.

[0031] In some embodiments of the present invention, there is provided a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof: [ka] In the formula, R1, R2, and R3 are independently selected from a hydrogen atom and a C1-C6 alkyl group, and R1, R2, and R3 are not simultaneously hydrogen atoms, or R1 and R2 are bonded to each other to form a ring shown below, and R3 is a hydrogen atom or does not exist; [ka] Optionally, the ring formed by R1 and R2 is substituted with m R', where m is selected from 0 or 1, and R' is selected from a hydrogen atom, an amino group, a carboxy group, or a C1 to C6 alkylcarboxy group.

[0032] In some embodiments of the present invention, there is provided a compound represented by general formula (III), or a pharmaceutically acceptable salt thereof: [ka] In the formula, R1 and R2 are bonded to form a ring shown below, and R3 is a hydrogen atom or is absent. [ka] Optionally, the ring formed by R1 and R2 is substituted with m R', where m is selected from 0 or 1, and R' is selected from a hydrogen atom, an amino group, a carboxy group, or a C1-C6 alkylcarboxy group.

[0033] In some embodiments of the present invention, the compounds shown below are provided, but are not limited to the specific compounds shown below. [ka] [ka] [ka] [ka] [ka]

[0034] In some embodiments of the present invention, pharmaceutical compositions are provided comprising at least one compound of the invention described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

[0035] In some embodiments of the present invention, there is provided use of a compound of the present invention described herein or a pharmaceutically acceptable salt thereof, and the above-mentioned pharmaceutical composition in the manufacture of a POLRMT inhibitor or a medicament for a disease associated with abnormally high expression of POLRMT due to oxidative phosphorylation.

[0036] In some embodiments of the present invention, there is provided the use of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof as described herein, and the pharmaceutical composition as described above, in the manufacture of a medicament for treating and / or preventing cancer, preferably in the manufacture of a medicament for treating and / or preventing melanoma, metastatic melanoma, pancreatic cancer, pancreatic ductal adenocarcinoma, prostate cancer, lung cancer, hepatocellular carcinoma, lymphoma, leukemia, myeloma, breast cancer, glioma, glioblastoma, cervical cancer, renal cancer, colorectal cancer or ovarian cancer.

[0037] (Second technical solution) The present invention provides a benzopyrone compound represented by the general formula (I') and a pharmaceutically acceptable salt thereof.

[0038] Another object of the present invention is to provide a pharmaceutical composition comprising any of the above compounds, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Another object of the present invention is to provide a use of a compound of the above general formula or a pharmaceutically acceptable salt thereof as a POLRMT inhibitor or in the manufacture of a medicament for a disease associated with abnormally high expression of POLRMT due to oxidative phosphorylation.

[0039] Another object of the present invention provides the use of a compound of the above general formula or a pharmaceutically acceptable salt thereof in a medicament for treating and / or preventing cancer, such as melanoma, metastatic melanoma, pancreatic cancer, pancreatic ductal adenocarcinoma, prostate cancer, lung cancer, hepatocellular carcinoma, lymphoma, leukemia, myeloma, breast cancer, glioma, glioblastoma, cervical cancer, renal cancer, colorectal cancer or ovarian cancer. Another object of the present invention is to provide a method for preparing compounds of the above general formula.

[0040] In some embodiments of the present invention, there is provided a compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof: [ka] In the formula, ring A is [ka] are randomly selected from *The carbon configuration is R or S, Ring A is optionally substituted by any one or more of R'1, R'2, R'3, R'4 and R'5; The R'1, R'2, R'3, R'4 and R'5 are each independently a hydrogen atom, a halogen atom, a carboxyl group and C 1~6 any group independently selected from alkylcarboxy groups; R4 and R5 are hydrogen atoms, halogens, and C 1~6 Any group is independently selected from the alkyl groups.

[0041] In some embodiments of the present invention, there is provided any compound selected from the following, or a pharmaceutically acceptable salt thereof: [ka] The salt is optionally a sodium, potassium or ammonium salt.

[0042] [Table β-1: A1-1 series compounds] [Table 1]

[0043] [Table β-2: A2-1 series compounds] [Table 2]

[0044] [Table β-3: A1-2 series compounds] [Table 3]

[0045] [Table β-4: A2-2 series compounds] [Table 4]

[0046] [Table β-5: A1-3 series compounds] [Table 5]

[0047] [Table β-6: A2-3 series compounds] [Table 6]

[0048] [Table β-7: A1-4 series compounds] [Table 7]

[0049] [Table β-8: A2-4 series compounds] [Table 8]

[0050] (Third technical solution) The present invention provides a benzopyrone compound, or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated product thereof, or a hydrate thereof, or a solvate thereof, [ka] wherein X1 and X2 are each independently selected from O or an NH group; Y is selected from a CR group or N; wherein R is H or a C1-C3 alkyl group; R1 and R1' may be the same or different and are each independently selected from hydrogen, an alkyl group, a cycloalkyl group, an aryl group, a heterocyclyl group, or a heteroaryl group; L1 and L3 are each independently selected from -O-, -S-, -NR3-, -CR2R3-, -CR2(R3), -CO-, -SO- or -SO2- groups; L2 is a direct bond, -CR2R3-, -CR2(R3)- or -C(R2R3)-, where R2 is selected from H or a C1-C4 chain alkyl group, and R3 is selected from H or a C1-C4 chain alkyl group, or R2 and R3 in one pair of -CR2(R3) together form one oxyylidene; R4, R5 and R6 are H, halogen, -C-OR8(R9), -CR8(R9), -CN, -NO2, -OR8, -NR8R9, -SR8, -COR8, -SOR8, -S02R8, -NR8COR9, -CONR8R9, -OCOR8, -COOR8, -OCONR8R9, -NR8CONR9R, respectively. 10 , -NR8COOR9, -NR8SO2R9, -SO2NR8R9, -OSO2R8, -SO3R8, a chain alkyl group, a heterochain alkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkene group, an alkyne group, an aryl group or a heteroaryl group, or an aromatic fused heterocyclyl group, wherein R8, R9, R 10 are each independently selected from H, a linear alkyl group, a heterocyclic alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, wherein the linear alkyl group, the heterocyclic alkyl group, the cycloalkyl group, the heterocycloalkyl group, the aryl group, or the heteroaryl group is independently selected from one or more R 11 and R 11is selected from halogen, cyano, hydroxy, mercapto, ether, nitro, alkoxy, amino, amine, carboxy, sulfonic acid, ester, acyloxy, amide, sulfonate ester, sulfonamide, linear alkyl, heterocyclic alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or aromatic fused heterocyclyl, wherein each linear alkyl, heterocyclic alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or aromatic fused heterocyclyl group is independently substituted by one or more halogen, cyano, hydroxy, mercapto, ether, nitro, alkoxy, amino, amine, carboxy, sulfonic acid, ester, amide, sulfonate ester, sulfonamide, alkyl, or haloalkyl group; or R4 and R5 together form an oxyylidene; Or, any two or three of R4, R5 and R6, together with the carbon atom bonded to L3, form a cyclic group A bonded to L3. [ka] wherein the cyclic group A is an arylcyclyl group, a saturated or unsaturated cycloalkyl group, a monoheterocyclyl group, a fused heterocyclyl group, a benzoheterocyclyl group, a spirocyclic group, a bridged ring group, and the like, and ... 11 any one cyclic group is selected from cyclic groups substituted by W is hydrogen, H, alkyl group, -CR 8a R 9a R 10a , -NR 8a R 9a , -OR 10a or a cyclic group B1 containing a carbon atom and attached to the benzopyrone ring by said carbon atom, substituted by one or more R7. [ka] or a cyclic group B2 containing a nitrogen atom and bonded to the benzopyrone ring by the nitrogen atom [ka] where R 8a , R 9a and R 10a are each independently selected from H, halogen, alkyl groups, cyano groups, hydroxy groups, mercapto groups, ether groups, nitro groups, alkoxy groups, amino groups, amine groups, carboxy groups, sulfonic acid groups, ester groups, acyloxy groups, amide groups, sulfonate ester groups, sulfonamide groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, and aromatic fused heterocyclyl groups, and the cyclic group B1 and cyclic group B2 are each independently selected from cycloalkyl groups, heterocycloalkyl groups, aryl groups, and heteroaryl groups.

[0051] Here, R7 is H, halogen, -CN, -NO2, -OR8, -NR8R9, -SR8, -COR8, -SOR8, -SOR8, -NR8COR9, -CONR8R9, -OCOR8, -COOR8, -OCONR8R9, -NR8CONR9R 10 , -NR8COOR9, -NR8SO2R9, -SO2NR8R9, -OSO2R8, -SO3R8, a chain alkyl group, a heterochain alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl or heteroaryl group, or an aromatic fused heterocyclyl group, preferably selected from a halogen, an alkyl group, a cyano group, a hydroxy group, a mercapto group, an ether group, a nitro group, an alkoxy group, an amino group, an amine group, a carboxy group, a sulfonic acid group, an ester group, an amide group, an acyloxy group, a sulfonate ester group, a sulfonamide group, a cycloalkyl group, a heterocycloalkyl group, an aryl or heteroaryl group, and wherein each chain alkyl group, heterochain alkyl group, cycloalkyl group, heterocycloalkyl group, aryl or heteroaryl group, or aromatic fused heterocyclyl group is independently selected from one or more R 11 and R, R and R 10The meaning of R8, R9 and R 10 is exactly the same as the meaning of However, formula (I) does not include the following compounds: [ka]

[0052] In one embodiment of the present invention, various types of benzopyrone compounds, preparation methods, and uses thereof in the manufacture of drugs used as POLRMT inhibitors are specifically provided as shown in Table γ-1 below.

[0053] [Table γ-1: Various types of benzopyrone compounds] [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4]

[0054] [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5] Table 10-6

[0055] Table 11

[0056] Table 12

[0057] Table 13

[0058] Table 14

[0059] Table 15-1 Table 15-2

[0060] Table 16

[0061] Table 17

[0062] Table 18

[0063] Table 19-1 Table 19-2

[0064] Table 20

[0065] Table 21

[0066] Table 22-1 Table 22-2 Table 22-3

[0067] Table 23-1 Table 23-2

[0068] Table 24-1 Table 24-2 Table 24-3

[0069] Table 25

[0070] Table 26

[0071] Table 27

[0072] Table 28

[0073] Table 29

[0074] Table 30

[0075] Table 31

[0076] Table 32

[0077] Table 33

[0078] Table 34

[0079] Table 35

[0080] [Table 36]

[0081] (Terminology of the present invention) The following terms are used to describe the present invention. As understood by those skilled in the art, terms not specifically defined should be understood to accord with the meaning given in the context of the term as used in the present invention.

[0082] As used herein, the term "alkyl group" refers to a saturated aliphatic hydrocarbon group, and the term includes straight-chain and branched hydrocarbon groups. For example, m~n The term "alkyl group" refers to an alkyl group having m to n carbon atoms (m and n are integers), such as C 1~6 It is an alkyl group. 1~6 The term "alkyl group" refers to an alkyl group having 1 to 6 carbon atoms, for example, an alkyl group having 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and includes, but is not limited to, a methyl group, an ethyl group, a propyl group (e.g., n-propyl group, isopropyl group), a butyl group (e.g., n-butyl group, isobutyl group, tert-butyl group), a pentyl group (e.g., n-pentyl group, isopentyl group, neopentyl group), a hexyl group (e.g., n-hexyl group), and the like.

[0083] In the present invention, X n , L n , R n , R na The subscript numbers and / or letters "n" or "na" in the formula are merely numbers used to distinguish different groups (or substituents, or atoms) and do not represent the number of these groups, for example, X1, X2, R2, R 2a、 L1, L2, L3, R3, R3, R4, R5, R6, R7, R8, R9, R 10 , R 8a , R 9a , R 10a , R11 The subscript numbers and / or letters (1, 2, 2a, etc.) in the substituents such as are merely numbers used to distinguish between different substituents, groups, or atoms. Specifically, non-limiting examples of bonding modes for these R substituents are as follows:

[0084] For example, "-C(R2R3)-" can refer to a form in which R2 is directly bonded to a C atom of a group, R3 is bonded to R2, and R3 is not directly bonded to the C atom, and the structural formula is: [ka] and For example, "-CR2R3-" can refer to the structure -C-R2-R3-; For example, "-CR8(R9)" can refer to a structure in which R9 is bonded only to the C atom, e.g., [ka] , including For example, "-C-OR(R)" can refer to a structure in which R is bonded directly to a carbon atom and is not bonded to R; For example, "-NR3-" means [ka] can point to, For example, "-NR8R9" means: [ka] can be pointed to.

[0085] As used herein, the term "oxo" refers to "O=".

[0086] The term "halogen" as used in the present invention refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0087] The term "carboxy group" as used herein refers to -COOH.

[0088] As used herein, the term "alkylcarboxy" refers to an alkyl group having a carboxy substituent.

[0089] The term "heterocyclyl group" as used herein refers to any group formed by a saturated or unsaturated oxygen heterocycle, nitrogen heterocycle, or sulfur heterocycle, and examples thereof include heterocycloalkyl groups and heteroaryl groups, including heterocycloalkyl groups such as oxiranyl group, oxetanyl group, aziridinyl group, azetidinyl group, and thietanyl group, and hydrogenated aromatic heterocyclic groups such as tetrahydrofuryl group, tetrahydropyrrolyl group, tetrahydrothienyl group, tetrahydropyranyl group, piperidinyl group, tetrahydrothiopyranyl group, dioxanyl group, piperazinyl group, hexahydropyrazinyl group, morpholinyl group, and dithianyl group, but are not limited thereto. The term "heteroaryl group" includes 5-membered heteroaryl groups, 6-membered heteroaryl groups, and benzoheteroaryl groups, but are not limited thereto, for example, furyl group, pyrrolyl group. , thienyl group, pyrazolyl group, imidazolyl group, oxazolyl group, thiazolyl group, isothiazolyl group, pyridyl group, oxygen-containing imidazolyl group or pyrazolyl group, pyranyl group, thiopyranyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, piperazinyl group, indolyl group, benzimidazolyl group, carbazolyl group, thiazolinyl group, quinolinyl group, isoquinolinyl group, purinyl group, acridinyl group, phenanthyl group, Heterocyclyl groups include any one of naphthyl and phenothiazinyl groups or partially hydrogenated aromatic heterocyclic groups thereof, benzoheterocyclyl groups such as benzofuryl, benzothienyl, benzopyrrolyl, indolyl, quinolinyl, isoquinolinyl, benzopyranyl, and groups formed by benzo-γ-pyrone, and fused-ring heterocyclyl groups, and heterocyclic-fused heterocyclyl groups such as purinyl. The "aryl group" refers to any one of phenyl, naphthyl, anthryl, and phenanthryl groups. The "heteroaryl group" is also referred to herein as an "aromatic hetero group," "heteroarylcyclyl group," or "arylheterocyclyl group," and refers to any one of the above aryl groups in which a carbon atom is replaced with an oxygen atom or a nitrogen atom, such as an anthraquinone group.

[0090] The term "benzopyrone-based compounds" refers to compounds containing a benzopyrone ring, a structure in which one carbon atom on the benzene ring in the benzopyrone ring is replaced with a nitrogen atom, a derivative structure formed by replacing one of the two oxygen atoms on the pyrone ring in the benzopyrone ring with a nitrogen atom, and any of the various structures formed by replacing the above-mentioned various structures. The term "coumarin ring" refers to the benzopyrone ring in the "benzopyrone-based compounds," and includes a structure in which one carbon atom on the benzene ring is replaced with a nitrogen atom or a structure in which one of the two oxygen atoms on the pyrone ring is replaced with a nitrogen atom.

[0091] The term "pharmaceutically acceptable salt" as used herein refers to a salt of a compound of the present invention prepared from a compound having a specific substituent discovered in the present invention and a pharmaceutically acceptable acid or base.

[0092] The term "pharmaceutically acceptable carrier" as used herein refers to any pharmaceutical carrier or medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and does not cause toxicity or side effects to the host or patient, and representative carriers include water, oil, vegetable, mineral, paste bases, lotion bases, ointment bases, etc. These bases include suspending agents, thickeners, skin penetration enhancers, etc.

[0093] [Manufacturing example] Hereinafter, in order to further explain the preparation of the benzopyrone compound of the present invention and its technical effect as a drug that specifically inhibits POLRMT, examples will be given in detail.

[0094] [First Manufacturing Example (including the first technical solution embodiment)] [Production Example (1) 1: Compound α-1] [ka] In step 1, α-1a (2.03 g, 20.3 mmol) and dry tetrahydrofuran (20 mL) were added to a 100 mL three-neck flask protected with N2. After complete dissolution, the temperature was cooled to 0 °C. Lithium hexamethyldisilazide (0.5 mL, 2.0 M THF) was added dropwise. After the addition was complete, the reaction was allowed to proceed for 10 min. The temperature was then cooled to -78 °C, and bromine (1 mL, 20 mmol) was slowly added dropwise. The reaction was continued for 3 h while maintaining the temperature. The reaction mixture was monitored by TLC. Upon complete reaction, the reaction mixture was added dropwise to saturated aqueous sodium bicarbonate solution, extracted with diethyl ether (20 mL x 3), and the combined organic phases were washed with sodium thiosulfate solution and then saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product α-1b (3.58 g, 19.99 mmol, 98% yield).

[0095] In step 2, α-1c (20.62 g, 100 mmol) and methanesulfonic acid (65 mL) were added to a 200 mL single-neck flask in that order and thoroughly dissolved. After that, resorcinol (10.392 g, 94 mmol) was added, the temperature was raised to 45°C, and the reaction was continued for 4 hours. After that, the reaction mixture was monitored by TLC. When the raw materials had completely reacted, the reaction mixture was diluted with ethanol, water was added, and the mixture was stirred to precipitate a solid. The solid was then filtered to obtain intermediate α-1d (18.0 g, 71.35 mmol, 72% yield).

[0096] In step 3, α-1d (0.73 g, 2.89 mmol) and N,N-dimethylformamide (10 mL) were added to a 100 mL single-neck flask in this order. After dissolving, dicesium carbonate (2.36 g, 7.23 mmol) was added at room temperature. After the entire mixture was added, the reaction was allowed to proceed for 10 minutes. α-1b (0.52 g, 2.89 mmol) was added and the reaction was allowed to proceed for 4 hours. This was monitored by TLC. Upon complete reaction, the reaction mixture was diluted with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give product α-1 (0.32 g, 0.91 mmol, 32% yield). MS-ESI: [M+H] + Calculated value: 351.1, measured value: 351.4.

[0097] [Production Example (1) 2: Compound α-2] [ka] In step 1, α-2a (1 g, 7.14 mmol) and carbon tetrachloride (10 mL) were added to a 100 mL single-neck flask in this order, and after thorough dissolution, the mixture was stirred for 5 minutes. Bromine (0.3 mL, 5.71 mmol) was added dropwise and the reaction was allowed to proceed for 4 hours. The reaction was monitored by TLC. Upon completion of the reaction, the reaction solution was added dropwise to a saturated aqueous solution of sodium bicarbonate, extracted with ethyl acetate, and the organic phase was washed with a sodium thiosulfate solution and then with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated using a rotary evaporator. After that, the resulting product was purified using a rapid separation column to obtain α-2b (1.33 g, 6.07 mmol, 85% yield).

[0098] In step 2, α-1d (1.10 g, 4.36 mmol) and N,N-dimethylformamide (10 mL) were added to a 100 mL single-neck flask in this order and thoroughly dissolved. Dicesium carbonate (4.11 g, 12.6 mmol) was added at room temperature and the reaction was continued for 10 minutes. α-2b (1.33 g, 6.07 mmol) was then added and the reaction continued for 4 hours. The reaction mixture was monitored by TLC. Upon complete reaction, the reaction mixture was concentrated on a rotary evaporator, water was added to precipitate a solid, and the solid was filtered and purified by column chromatography to give the product α-2 (1.00 g, 2.56 mmol, 59% yield). MS-ESI: [M+H] + Calculated value: 391.1, measured value: 391.4. 1 H NMR(400MHz,DMSO-d6)δ 7.48-7.37(m,2H),7.34(t,J=7.3Hz,1H),7.23(d,J=7.4Hz,1H),6.98(t,J=2.5Hz,1H),6.92-6.78(m,2H),6.18(s,1H),5.34(qd,J=6. 8,2.3Hz,1H),2.77(ddd,J=11.2,7.8,3.3Hz,1H),2.11(d,J=2.1Hz,3H),1.78-1.58(m,4H),1.47(d,J=6.8Hz,3H),1.37-1.10(m,6H).

[0099] [Production Example (1) 3: Compound α-3] [ka] In step 1, α-3a (3 g, 34.83 mmol) and diethyl ether (87 mL) were added to a 250 mL single-neck flask in this order and dissolved thoroughly. Bromine (1.8 mL, 34.83 mmol) was then added dropwise at room temperature and the reaction was allowed to proceed for 4 hours. The reaction mixture was monitored by TLC. When the raw materials had completely reacted, the reaction mixture was added dropwise to a saturated aqueous solution of sodium bicarbonate, extracted with ethyl acetate, and the organic phase was washed with a sodium thiosulfate solution and then with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to obtain the crude product α-3b (4.6 g, 27.87 mmol, 80% yield), which could be used directly in the next step without further purification.

[0100] In step 2, α-1d (1.21 g, 4.8 mmol) and N,N-dimethylformamide (20 mL) were added to a 200 mL single-neck flask in this order. After thorough dissolution, dicesium carbonate (4.07 g, 12.5 mmol) was added at room temperature and the reaction was continued for 10 minutes. α-3b (1.32 g, 8 mmol) was added and the reaction continued for 8 hours. The reaction mixture was monitored by TLC. Once the starting materials were completely reacted, the reaction mixture was filtered, the filtrate was diluted with water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, and then purified using a rapid separation column to obtain the desired product (0.70 g, 2.08 mmol, 43% yield). MS-ESI: [M+H] + Calculated value: 337.1, measured value: 337.4. 1 H NMR(400MHz,DMSO-d6)δ 7.38(dt,J=29.0,8.3Hz,3H),7.24(d,J=7.7Hz,1H),7.01(s,1H),6.86(s,2H),6.19(s,1H),5.1 7(q,J=7.0Hz,1H),2.84-2.52(m,2H),2.11(s,3H),1.47(d,J=6.0Hz,3H),0.94(t,J=6.2Hz,3H).

[0101] [Production Example (1) 4: Compound α-4] [ka] In step 1, α-4a (7.00 g, 33.90 mmol) was dissolved in perchloric acid (20 mL) in a dry 100 mL three-neck flask, and then resorcinol (4.50 g, 40.7 mmol) was added. The reaction mixture was allowed to react at room temperature for 16 hours until complete. After completion of the reaction, the mixture was quenched by adding water (40 mL) in an ice-water bath. The mixture was extracted with ethyl acetate, dried, and concentrated. The residue was purified by silica gel column chromatography to give α-4b (6.94 g, 27.51 mmol, 81.1% yield). MS-ESI: [M+H] + Calculated value: 253.1, measured value: 253.0. 1 H NMR(600MHz,DMSO-d6)δ 10.64(s,1H),7.44-7.37(m,2H),7.34(t,J=7.4,1H),7.23(d,J=7.5,1H), 6.84-6.79(m,2H),6.73(dd,J=8.7,2.3Hz,1H),6.09(s,1H),2.11(s,3H).

[0102] In step 2, in a dry 50 mL three-neck flask, compound α-4c (1.00 g, 7.40 mmol) was dissolved in acetic acid:carbon tetrachloride = 1:1 (10 mL), and then bromine (3.55 g, 22.21 mmol) was added. The reaction mixture was allowed to react at room temperature for 16 hours until the reaction was complete. After the reaction was completed, the reaction was quenched by adding saturated sodium sulfite solution (10 mL) and saturated sodium bicarbonate solution (20 mL) in an ice-water bath. The mixture was extracted with ethyl acetate, dried, and concentrated to give crude product α-4d (1.10 g, 5.14 mmol, 63.39% yield) as the product. MS-ESI: [M+H] + Calculated value: 214.1, measured value: 214.0.

[0103] In step 3, compound α-4d (407.0 mg, 1.9 mmol), α-4b (400.0 mg, 1.59 mmol), and potassium carbonate (438.0 mg, 3.17 mmol) were dissolved in acetonitrile (10 mL) in a dry 50 mL three-neck flask and allowed to react at room temperature for 16 hours until complete. After completion of the reaction, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate, dried, and concentrated. The residue after concentration under reduced pressure was purified by silica gel column chromatography to give the product as a white solid, α-4 (69.0 mg, 0.18 mmol, 11% yield). MS-ESI: [M+H] + Calculated value: 386.4, measured value: 386.0. 1 H NMR(600MHz,DMSO-d6)δ 8.83(d,J=4.7,1H),8.09(t,J=7.7,1H),8.01(d,J=7.8,1H),7.81-7.75(m,1H),7.43-7.37(m,2H),7.33(q,J=7.3,1H), 7.25-7.20(m,1H),6.91-6.79(m,3H),6.43(q,J=6.8Hz,1H),6.17(s,1H),2.10(d,J=5.1Hz,3H),1.63(d,J=6.8Hz,3H).

[0104] [Production Example (1) 5: Compound α-5] [ka] In step 1, in a dry 50 mL three-neck flask, compound α-5a (500.0 mg, 3.70 mmol) was dissolved in diethyl ether (5 mL), and then bromine (1.18 mg, 7.4 mmol) was added. The reaction mixture was reacted at 50°C for 20 hours until the reaction was complete. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain crude product α-5b (500 mg, 2.34 mmol, 63.1% yield). MS-ESI: [M+H] + Calculated value: 214.1, measured value: 214.0.

[0105] In step 2, compound α-5b (500 mg, 2.34 mmol), α-4b (250 mg, 0.99 mmol), and N,N-diisopropylethylamine (645.0 mg, 5.0 mmol) were dissolved in acetone (10 mL) in a dry 50 mL three-neck flask and allowed to react at room temperature for 16 hours until complete. After completion of the reaction, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate, dried, and concentrated. The residue after concentration under reduced pressure was first purified by silica gel column chromatography and then by high-pressure preparative chromatography to obtain product α-5 (70 mg, 0.18 mmol, 18% yield, white solid). MS-ESI: [M+H] + Calculated value: 386.4, measured value: 386.0. 1 H NMR(600MHz,DMSO-d6)δ 9.24(s,1H),8.87(d,J=4.2Hz,1H),8.41(dq,J=8.0,2.2Hz,1H),7.64(dd,J=8.0,4.8Hz,1H),7.45-7.37(m,2H),7.36-7.31(m,1H),7.2 5-7.22(m,1H),7.11(s,1H),6.93-6.87(m,2H),6.23(p,J=6.7Hz,1H),6.20(s,1H),2.11(d,J=3.4Hz,3H),1.59(dd,J=6.8,1.3Hz,3H).

[0106] [Production Example (1) 6: Compound α-6] [ka] In step 1, in a dry 50 mL three-neck flask, compound α-6a (500 mg, 3.70 mmol) was dissolved in diethyl ether (5 mL), and then bromine (1.18 mg, 7.40 mmol) was added. The reaction mixture was reacted at 50° C. for 20 hours until the reaction was complete. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain crude product α-6b (500 mg, 2.34 mmol, 63% yield). MS-ESI: [M+H] +Calculated value: 214.06, measured value: 214.0.

[0107] In step 2, compound α-6b (500 mg, 2.34 mmol), α-4b (250.0 mg, 0.99 mmol), and N,N-diisopropylethylamine (645.0 mg, 5.0 mmol) were dissolved in acetone (10 mL) in a dry 50 mL three-neck flask and allowed to react at room temperature for 16 hours until complete. After completion of the reaction, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate, dried, and concentrated. The residue after concentration under reduced pressure was first purified by silica gel column chromatography and then by high-pressure preparative chromatography to obtain product α-6 (60.0 mg, 0.16 mmol, 16% yield, white solid). MS-ESI: [M+H] + Calculated value: 386.4, measured value: 386.0. 1 H NMR(600MHz,DMSO-d6)δ 8.86(d,J=17.4,4.7,2H),7.95-7.84(m,2H),7.45-7.37(m,2H),7.37-7.30(m,1H),7.26-7.21(m,1H),7.11 (d,J=2.0Hz,1H),6.92-6.86(m,2H),6.26-6.19(m,2H),2.11(d,J=3.7Hz,3H),1.57(dd,J=6.7,1.2Hz,3H).

[0108] [Production Example (1) 7: Compound α-7] [ka] In step 1, compound α-7a (4.00 g, 17.45 mmol) was dissolved in N,N-dimethylformamide (40 mL) in a dry 100 mL three-neck flask. Dimethylhydroxylamine hydrochloride (2.00 g, 20.90 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (7.96 g, 20.90 mmol), and N,N-diisopropylethylamine (6.75 g, 52.35 mmol) were then added. The reaction mixture was allowed to react at room temperature for 3 hours until complete. After completion, the reaction was quenched by adding water (40 mL). The mixture was extracted with ethyl acetate, dried, and concentrated. The residue, after concentration under reduced pressure, was purified by medium-pressure reverse-phase chromatography to give product α-7b (4.75 g, 17.44 mmol, 99% yield). MS-ESI: [M+H] + Calculated value: 273.2, measured value: 273.0.

[0109] In step 2, compound α-7b (4.50 g, 16.52 mmol) was dissolved in tetrahydrofuran (40 mL) in a dry 100 mL three-neck flask, and then ethylmagnesium bromide (1 M tetrahydrofuran solution) (24.80 mmol) was added. The reaction mixture was allowed to react at room temperature for 18 hours until the reaction was complete. After completion of the reaction, water (40 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate, dried, and concentrated. The residue after concentration under reduced pressure was purified by medium-pressure reverse-phase chromatography to give product α-7c (3.50 g, 14.50 mmol, 87% yield). MS-ESI: [M+H] + Calculated value: 242.3, measured value: 242.0.

[0110] In step 3, compound α-7c (2.00 g, 8.29 mmol) was dissolved in diethyl ether (10 mL) in a dry 50 mL three-neck flask, and then bromine (1.45 g, 9.1 mmol) was added. The reaction mixture was allowed to react at 40 °C for 4 hours until complete. After completion of the reaction, the mixture was concentrated under reduced pressure to give crude product α-7d (1.50 g, 6.84 mmol, 82% yield). MS-ESI: [M+H] + Calculated value: 220.1, measured value: 220.0.

[0111] In step 4, in a dry 50 mL three-neck flask, the crude product of compound α-7d (650 mg, 2.95 mmol) was dissolved in acetone (20 mL), followed by the addition of α-4b (500.0 mg, 1.98 mmol) and potassium carbonate (821 mg, 5.94 mmol). The reaction mixture was allowed to react at room temperature for 16 hours until complete. After completion of the reaction, water (20 mL) was added to quench the reaction, followed by extraction with ethyl acetate, drying, and concentration. The residue after concentration under reduced pressure was first purified by silica gel column chromatography and then by high-pressure preparative chromatography to obtain product α-7 (50.0 mg, 0.13 mmol, 4% yield, white solid). The resulting product was dissolved in acetonitrile, followed by the addition of dilute hydrochloric acid until the pH reached approximately 2, and then lyophilized to obtain the hydrochloride salt. MS-ESI: [M+H] + Calculated value: 392.4, measured value: 392.1. 1 H NMR(600MHz,DMSO-d6)δ 9.11(d,J=11.2Hz,1H),8.79(q,J=11.0Hz,1H),7.46-7.39(m,2H),7.35(t,J=7.5Hz, 1H),7.24(d,J=7.5Hz,1H),7.06-7.01(m,1H),6.91-6.83(m,2H),6.21(s,1H),5.49-5 .33(m,1H),3.27(dd,J=31.6,12.7Hz,2H),3.18-3.12(m,1H),2.97-2.87(m,2H),2.1 7-2.08(d,J=3.2Hz,4H),1.85-1.77(m,1H),1.74-1.61(m,2H),1.49(d,J=6.8Hz,3H).

[0112] [Production Example (1) 8: Compound α-8] [ka] In step 1, α-8a (5.00 g, 20.55 mmol), methoxy(methyl)amine hydrochloride (2.203 g, 22.61 mmol), 1-propylphosphonic anhydride (13.07 g, 41.1 mmol), and triethylamine (6.23 g, 61.65 mmol) were dissolved in N,N-dimethylformamide (35 mL) in a dry 100 mL three-neck flask and reacted at room temperature for 1-2 h. The reaction mixture was monitored by LCMS. Once the starting materials were completely consumed, the mixture was diluted with water and extracted with ethyl acetate to give white, flocculent α-8b (5.32 g, 18.6 mmol, 75.96% yield, 95% purity). MS-ESI: [M+H] + =287.2

[0113] In step 2, α-8b (3.60 g, 12.59 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL) in a dry 100 mL three-neck flask, and ethylmagnesium bromide (2 M, 18.89 mL, 37.76 mmol) was added dropwise in an ice-salt bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 14 hours. The reaction was quenched by adding 10% hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product, which was purified by silica gel column chromatography (PE:EA = 4:1, R f =0.67, iodine fumigation) to give a colorless oily product α-8c (2.74 g, 10.72 mmol, yield 51.82%, purity 93%). MS-ESI: [M+H] + =256.2

[0114] In step 3, α-8c (2.00 g, 7.8 mmol) was dissolved in chloroform (30 mL) in a dry 100 mL three-neck flask, and bromine (1.88 g, 11.76 mmol) was added dropwise in an ice-salt bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 14 h. LCMS and TLC monitoring indicated that no starting material remained (no color development occurred). The reaction was quenched by pouring the reaction mixture into saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and spun to dryness to give crude compound 4, a pale yellow oil, α-8d (1.85 g, 5.52 mmol, 44.87% yield, 80.34% purity). MS-ESI: [M+H] + =234.2

[0115] In step 4, compound A1-1-1c (300.0 mg, 1.03 mmol) was dissolved in acetonitrile (10 mL), and α-8d (483.0 mg, 2.06 mmol) and potassium carbonate (427.3 mg, 3.09 mmol) were added. The reaction was allowed to proceed at room temperature for 2 hours. The reaction status was monitored by LCMS and TLC. After 16 hours, the mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and spun to dryness to give the crude product, which was purified by medium-pressure and preparative HPLC to give compound α-8 (42.0 mg, 87.40 μmol, 8.5% yield). MS-ESI: [M+H] + =444.3

[0116] [Production Example (1) 9: Compound α-9] [ka] In step 1, in a dry 500 mL three-neck flask, α-9a (10.00 g, 46.93 mmol) was dissolved in 35 mL of N,N-dimethylformamide, and cuprous cyanide (5.50 g, 61.40 mmol) was added. The mixture was refluxed and stirred for 6 h. Upon returning to room temperature, ferric chloride (4.70 g, 28.97 mmol) dissolved in water and 37% aqueous hydrochloric acid (10 mL) were added. The reaction was heated to 80 °C and stirred for 30 min, then cooled to room temperature and stirred overnight. The reaction was complete when the starting material was almost completely removed, as monitored by LCMS and TLC. The reaction mixture was diluted with water and extracted with tert-butyl methyl ether. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and passed through a normal phase column (PE:EA=10:1) to give a yellow solid α-9b (6.00 g, 37.69 mmol, 80% yield). 1 H NMR(400MHz,DMSO-d6)δ 8.39(td,J=1.7,0.6Hz,1H),8.24(ddd,J=7.9,1.8,1.2Hz,1H),8.10(dt,J=7.8,1. 3Hz,1H),7.74(td,J=7.8,0.6Hz,1H),3.11(q,J=7.1Hz,2H),1.09(t,J=7.1Hz,3H).

[0117] In step 2, 30 mL of methanol was added to a dry 250 mL three-neck flask and cooled to -78 °C. Acetyl chloride (30 mL) was added dropwise, and α-9b (6.00 g, 37.69 mmol) was added to the reaction flask. The temperature was slowly raised to room temperature, cautiously monitoring the release of HCl gas from the reaction mixture at approximately -40 °C, and the mixture was stirred for 2 h. The reaction mixture was monitored by LCMS. Upon completion, the reaction mixture was concentrated by rotary evaporation to give the imine intermediate. A 0.5% aqueous TFA solution was added to the flask, and the mixture was stirred overnight at room temperature. The mixture was then rotary evaporated and concentrated. The mixture was then passed through a normal-phase column (PE:EA = 10:1). The spot above the starting material was the product, affording α-9c (1.00 g, 5.2 mmol, 13.8% yield) as a white solid. MS-ESI: [M+H] + =193.0 1H NMR(400MHz,DMSO-d6)δ 8.39(s,1H),8.12-7.99(m,2H),7.61(t,J=7.8Hz,1H),3.82(s,3H),3.10(q,J=7.1Hz,2H),1.10(t,J=7.2Hz,3H).

[0118] In step 3, α-9c (800 mg, 4.16 mmol) was dissolved in 10 mL of ultra-dry dichloromethane in a dry 50 mL three-neck flask and protected with nitrogen. Bromine (3.33 g, 20.83 mmol, 1.06 mL) and hydrogen bromide (244 μL, 4.16 mmol) were added at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 2 h. LCMS indicated complete consumption of the starting material, indicating complete reaction. The mixture was extracted with saturated sodium bicarbonate, separated, dried over anhydrous sodium sulfate, and the organic phase was directly concentrated to give α-9d (800 mg, 2.95 mmol, 70% yield) as a yellow oil. The mixture was dried by removing water with an oil pump and used directly in the next step. MS-ESI: [M+H] + =271.2 1 H NMR(400MHz,DMSO-d6)δ 8.54(td,J=1.8,0.5Hz,1H),8.35-8.28(m,1H),8.26-8.17(m,1H),7.73(td, J=7.8,0.6Hz,1H),5.87(p,J=6.2Hz,1H),3.91(s,3H),1.80(d,J=6.5Hz,3H).

[0119] In step 4, compound α-9d (300.0 mg, 1.11 mmol) was dissolved in 6 mL of N,N-dimethylformamide in a dry 50 mL three-neck flask, and A1-1-1c (450 mg, 1.55 mmol) and dicesium carbonate (840 mg, 2.58 mmol) were added. The mixture was protected with nitrogen and stirred at room temperature for 2 h. After completion of the reaction, monitored by LCMS, water and ethyl acetate were added, washed with saturated brine, and the organic phase was concentrated to give the crude product. The crude product was dissolved in N,N-dimethylformamide and purified by MPLC to give a yellow solid α-9e (310 mg, 0.64 mmol, 41.5% yield). MS-ESI: [M+H] + =481.2 1 H NMR (400 MHz, DMSO-d6) δ 8.55(t,J=1.8Hz,1H),8.36(dq,J=7.8,1.6Hz,1H),8.26(dt,J=7.8,1.4Hz,1 H),7.76(t,J=7.8Hz,1H),7.69(dt,J=8.9,2.3Hz,1H),7.55(ddd,J=8.6,6.1, 1.7Hz,1H),7.42(tdd,J=8.5,4.4,2.5Hz,1H),7.10(dd,J=6.4,2.4Hz,1H),6. 98-6.84(m,2H),6.35-6.23(m,2H),3.90(s,3H),1.59(dd,J=6.8,1.1Hz,3H).

[0120] In step 5, α-9e (200.0 mg, 442 μmol) was added to a dry 100 mL three-neck flask and dissolved in 1 mL of tetrahydrofuran. 2 mL of aqueous hydrochloric acid (6 M) was added, and the mixture was heated to 100 °C and stirred for 16 h. LCMS detection confirmed the reaction was complete. The reaction mixture was concentrated and spin-dried to obtain the crude product, which was dissolved in N,N-dimethylformamide and purified by MPLC to give a white solid α-9 (55.0 mg, 112.5 μmol, 26% yield). MS-ESI: [M+H] + =467.1 1 H NMR(400MHz,DMSO-d6)δ 8.50(t,J=1.7Hz,1H),8.15(dt,J=7.6,1.4Hz,1H),8.01(dq,J=7.8,1.7Hz,1H),7.68( dt,J=8.9,2.7Hz,1H),7.55(ddd,J=8.8,6.1,2.9Hz,1H),7.47(t,J=7.6Hz,1H),7.45-7 .38(m,1H),7.01(dd,J=4.6,2.4Hz,1H),6.94(dd,J=8.9,1.5Hz,1H),6.87(ddd,J=8.9, 6.4,2.4Hz,1H),6.29(d,J=1.4Hz,1H),6.27-6.16(m,1H),1.58(dd,J=6.7,1.2Hz,3H).

[0121] [Production Example (1) 10: Compound α-10] [ka] In step 1, compound α-10a (5.00 g, 26.85 mmol) was dissolved in tert-butanol (70 mL) in a dry 100 mL three-neck flask, and 4-dimethylaminopyridine (1.31 g, 10.74 mmol) and di-tert-butyl dicarbonate (15.24 g, 69.82 mmol) were added. The reaction was allowed to proceed at room temperature for 2 hours. The complete reaction (PE:EA = 4:1, R f =0.77, iodine fumigation). The reaction mixture was spin-dried, dissolved in ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium bicarbonate solution, and saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product α-10b (6.4 g, 26.41 mmol, yield 98%, purity 80%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 3.58(s,3H),2.33-2.20(m,1H),2.20-2.08(m,1H),1.96-1.81(m,4H),1.38(s,9H),1.36-1.26(m,4H).

[0122] In step 2, compound α-10b (6.40 g, 26.41 mmol) was dissolved in a mixed solvent of methanol (128 mL) and water (77 mL) in a dry 250 mL three-neck flask. Sodium hydroxide (5.28 g, 132.06 mmol) was added and the mixture was allowed to react at room temperature for 1 h. Most of the methanol was removed by rotary evaporation under reduced pressure, and the mixture was washed twice with ethyl acetate. The aqueous phase was adjusted to pH 2-3 with concentrated hydrochloric acid, and then extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain a white solid, α-10c (5.46 g, 23.92 mmol, 90% yield, 100% purity). 1H NMR(400MHz,DMSO-d6)δ 12.05(s,1H),2.23-.04(m,2H),1.97-1.79(m,4H),1.38(s,8H),1.34-1.26(m,4H).

[0123] In step 3, compound α-10c (5.43 g, 23.79 mmol), methoxy(methyl)amine hydrochloride (2.55 g, 26.16 mmol) were dissolved in N,N-dimethylformamide (55 mL) in a dry 100 mL three-neck flask. Benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (9.92 g, 26.16 mmol), 1-hydroxybenzotriazole (3.53 g, 26.16 mmol), and N,N-diisopropylethylamine (15.37 g, 118.93 mmol) were added in an ice bath and the mixture was allowed to react at room temperature for 2 hours. The reaction was quenched by adding water and extracted three times with ethyl acetate. The combined organic phases were washed with 1 M hydrochloric acid, 1 M sodium hydroxide, and saturated brine, respectively, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product, which was purified by silica gel column chromatography (PE:EA = 4:1, R f =0.46, iodine fumigation) to give α-10d (5.96 g, 21.96 mmol, yield 92%, purity 95%) as a colorless oil.

[0124] In step 4, compound α-10d (5.46 g, 20.12 mmol) was dissolved in anhydrous tetrahydrofuran (23 mL) in a dry 100 mL three-neck flask and added dropwise to ethylmagnesium bromide (2 M, 25.15 mL, 50.30 mmol) in an ice-salt bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 hour. The reaction was quenched by adding 10% hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product, which was purified by silica gel column chromatography (PE:EA = 4:1, R f =0.67, iodine fumigation) to give α-10e (4.21 g, 17.52 mmol, yield 87%, purity 95%) as a colorless oil.

[0125] In step 5, compound α-10e (500 mg, 2.08 mmol) was dissolved in methanol (7 mL) in a dry 50 mL three-neck flask, 48% hydrobromic acid (15 μL) was added, and bromine (339 mg, 2.12 mmol, 108.7 μL) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 16 hours. TLC showed that no starting material remained (no color development of the product). The reaction solution was quenched by pouring into saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and spun dry to give the crude compound α-10f (596.0 mg, 1.87 mmol, 89% yield, 50% purity) as a pale yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 4.52 (qd, J = 6.8, 1.4 Hz, 1H), 2.89-2.76 (m, 1H), 2.37-2.13 (m, 1H), 2.12-1.90 (m, 4H), 1.73 (d, J = 6.8, Hz, 3H), 1.66-1.24 (m, 13H).

[0126] In step 6, in a dry 50 mL three-neck flask, compound α-10f (494.0 mg, 1.55 mmol) and A1-1-1c (300 mg, 1.03 mmol) were dissolved in N,N-dimethylformamide (7.5 mL), and dicesium carbonate (873 mg, 2.68 mmol) was added. The reaction was allowed to proceed at room temperature for 2 hours. The reaction was confirmed by LCMS as complete. The mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and spun dry to obtain the crude product. The crude product was purified by medium-pressure reverse-phase chromatography to yield a white solid, α-10g (211.0 mg, 379 μmol, 38% yield, 95% purity). MS-ESI: [M+Na] + =551.1

[0127] In step 7, compound α-10g (180 mg, 340 μmol) was dissolved in dichloromethane (2.7 mL) in a dry 50 mL three-neck flask, trifluoroacetic acid (0.9 mL) was added, and the mixture was allowed to react at room temperature for 1 h. The reaction was confirmed by LCMS to be complete. The reaction mixture was then spun dry, and the residue was dissolved in acetonitrile (1 mL). The pH was adjusted to 8-9 by adding saturated sodium bicarbonate. The mixture was purified by medium-pressure reverse-phase chromatography to give a white solid, α-10 (45 mg, 91 μmol, 26% yield, 98.31% purity). MS-ESI: [M-Na] - =471.2 1 H NMR(400MHz,DMSO-d6)δ 7.70(dd,J=8.6,2.2Hz,1H),7.57(ddd,J=8.6,6.1,1.4Hz,1H),7.43(tdd,J=8.5,2.6,1.0H z,1H),6.99(dd,J=4.1,2.5Hz,1H),6.95(dd,J=8.9,2.3Hz,1H),6.88-6.81(m,1H),6.31(s, 1H),5.36(qd,J=6.9,4.1Hz,1H),2.71-2.64(m,1H),1.94(dd,J=26.4,11.0Hz,2H),1.85-1 .83(m,1H),1.77-1.71(m,1H),1.65-1.63(m,1H),1.47(d,J=6.8Hz,3H),1.35-1.09(m,4H).

[0128] [Production Example (1) 11: Compound α-11] [ka] In step 1, α-11a (2.0 g, 8.29 mmol) and tetrahydrofuran (30 mL) were added to a dry 100 mL three-neck flask in that order. After dissolving, pyridinium bromide perbromide (2.92 g, 2.07 mmol) was added. After all the raw materials were added, the reaction was allowed to proceed at room temperature overnight and monitored by TLC until the raw materials were completely reacted. After the reaction was complete, the reaction system was filtered, and the filtrate was collected and concentrated on a rotary evaporator. It was then purified using a rapid separation column to obtain α-11b (2.08 g, 6.50 mmol, 78% yield).

[0129] In step 2, α-11b (1.00 g, 3.12 mmol), A1-1-1c (760.0 mg, 2.61 mmol), and dry acetone (30 mL) were added to a dry 100 mL three-neck flask in this order and thoroughly dissolved. After that, potassium carbonate (0.72 g, 5.21 mmol) and tetrabutylammonium iodide (0.96 g, 2.60 mmol) were added in this order. After all the raw materials were added, the temperature was slowly raised to 25°C, and the reaction was continued for 6 hours while maintaining the temperature. The reaction was monitored by TLC until the raw materials had completely reacted. After the reaction was completed, the reaction mixture was washed with water (30 mL) and then extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated using a rotary evaporator, and then purified using a rapid separation column to obtain α-11c (1.28 g, 2.42 mmol, yield 92%).

[0130] In step 3, α-11c (1.36 g, 2.56 mmol) was added to a dry, clean eggplant flask, followed by the slow dropwise addition of hydrogen chloride in ethyl acetate (3.0 M, 20 mL). The mixture was stirred at room temperature and the reaction progress was monitored by TLC. After the reaction was complete, a white suspension was obtained. The solid was filtered and dried to give the desired product, α-11 (1.10 g, 2.36 mmol, 92% yield, 97% purity). MS-ESI: [M+H] + =430.0 1H NMR(400MHz, methanol-d4)δ 7.50-7.42(m,2H),7.29(td,J=8.3,2.5Hz,1H),7.04(d,J=8.6Hz,1H),6 .99(s,1H),6.92(d,J=8.6Hz,1H),6.23(s,1H),5.24(d,J=6.7Hz,1H),3 .51-3.37(m,2H),3.31-3.23(m,2H),3.11(m,2H),2.24(d,J=14.4Hz,1H ),1.95(d,J=14.3Hz,1H),1.85(t,J=12.1Hz,2H),1.56(d,J=6.4Hz,3H).

[0131] [Production Example (1) 12: Compound α-12] [ka] In step 1, compound α-12a (5.00 g, 18.99 mmol), methoxy(methyl)amine hydrochloride (2.04 g, 20.89 mmol) were dissolved in N,N-dimethylformamide (50 mL) in a dry 100 mL three-neck flask. Benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (7.92 g, 20.89 mmol), 1-hydroxybenzotriazole (2.82 g, 20.89 mmol), and N,N-diisopropylethylamine (12.27 g, 94.95 mmol) were added in an ice bath. The reaction was allowed to proceed at room temperature for 16 hours. The reaction was detected by LCMS as complete. The reaction was quenched by adding water and extracted three times with ethyl acetate. The organic phases were combined, washed with 1 M hydrochloric acid, 1 M sodium hydroxide, and saturated brine, respectively, dried over anhydrous sodium sulfate, and spun to dryness to give the crude product, which was then subjected to medium-pressure reverse-phase chromatography to give α-12b (5.24 g, 17.10 mmol, yield 90%, purity 90%) as a colorless oil. MS-ESI: [M+H] + =307.1

[0132] In step 2, in a dry 100 mL three-neck flask, compound α-12b (5.30 g, 17.30 mmol) was dissolved in anhydrous tetrahydrofuran (21 mL) and added dropwise to ethylmagnesium bromide (2 M tetrahydrofuran, 21.63 mL, 43.25 mmol) in an ice-salt bath. After the addition was complete, the reaction was carried out at room temperature for 1 hour, and TLC (PE:EA=4:1, R f =0.41), indicating a complete reaction. The reaction was quenched by adding 10% hydrochloric acid and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and spun to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain α-12c (3.79 g, 13.76 mmol, yield 79%, purity 90%) as a colorless oil. MS-ESI: [M+H] + =276.0

[0133] In step 3, compound α-12c (500.0 mg, 1.82 mmol) was dissolved in methanol (7.5 mL) in a dry 50 mL three-neck flask, 48% hydrobromic acid (15 μL) was added, and bromine (296.0 mg, 1.85 mmol, 95 μL) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 16 hours, and the reaction was confirmed by LCMS. The reaction was quenched by pouring the reaction mixture into saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and spun dry to give the crude product α-12d (542.0 mg, 1.53 mmol, 84% yield, 70% purity) as a pale yellow oil. MS-ESI: [M+H] + =354.0

[0134] In step 4, in a dry 50 mL three-neck flask, compound α-12d (418 mg, 1.18 mmol, 70% purity) and compound A1-1-1c (160 mg, 550 μmol) were dissolved in N,N-dimethylformamide (4 mL), and dicesium carbonate (466 mg, 1.43 mmol) was added. The reaction was allowed to proceed at room temperature for 3 hours. The reaction was confirmed by LCMS to be complete. The mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product. The crude product was purified by medium-pressure reverse-phase chromatography to obtain α-12e (251.0 mg, 455 μmol, 82% yield, 95% purity) as a white solid. MS-ESI: [M+H] + =564.1

[0135] In step 5, compound α-12e (256 mg, 453.90 μmol) was dissolved in methanol (6 mL) in a dry 50 mL three-neck flask, and palladium hydroxide on carbon (78 mg, 20%) was added. After purging with hydrogen three times, the mixture was reacted at ambient pressure and room temperature for 1 h. The reaction was confirmed by LCMS to be complete. After filtration, the cake was washed with methanol, and the combined filtrate was spin-dried to give the crude product, which was purified by medium-pressure reverse-phase chromatography to give α-12f (132 mg, 307 μmol, 67% yield, 95% purity) as a white solid. MS-ESI: [M+H] + =430.0

[0136] In step 6, compound α-12f (110 mg, 255.89 μmol) was dissolved in N,N-dimethylformamide (2.2 mL) in a dry 50 mL three-neck flask, and tert-butyl bromoacetate (54.9 mg, 281.48 μmol) and triethylamine (28 mg, 281 μmol) were added. The reaction was allowed to proceed at room temperature for 2 hours. The reaction was confirmed by LCMS to be complete. The reaction mixture was purified by medium-pressure reverse-phase chromatography to give a white solid, α-12g (135 mg, 248 μmol, 96% yield, 99% purity). MS-ESI: [M+H] + =544.3,[M-t Bu] + =488.3

[0137] In step 7, compound α-12g (110 mg, 202.2 μmol) was dissolved in dichloromethane (1.8 mL) in a dry 50 mL three-neck flask, trifluoroacetic acid (0.6 mL) was added, and the reaction was allowed to proceed at room temperature for 4 hours. The reaction was confirmed by LCMS to be complete. The reaction mixture was then spun dry, and the residue was dissolved in acetonitrile (1 mL). The pH was adjusted to 8-9 by adding saturated sodium bicarbonate. The mixture was purified by medium-pressure reverse-phase chromatography to give α-12 (42 mg, 82 μmol, 40% yield, 95.37% purity) as a white solid. MS-ESI: [M-Na]-=486.2. 1 H NMR(400MHz,DMSO-d6)δ 7.70(ddd,J=8.9,2.6,1.0Hz,1H),7.57(ddd,J=8.6,6.1,1.6Hz,1H),7.43(tdd,J=8.5 ,2.6,1.2Hz,1H),7.04-7.00(m,1H),7.00-6.89(m,1H),6.85(ddd,J=9.1,6.9,2.5Hz, 1H),6.32(s,1H),5.38(qd,J=6.8,3.5Hz,1H),2.93(dd,J=24.8,11.2Hz,2H),2.73(s, 2H),2.71-2.64(m,1H),2.15-1.99(m,2H),1.88(d,J=12.5Hz,1H),1.61-1.43(m,6H). 19 F NMR(376MHz,DMSO-d6)δ 109.97(s,1F).

[0138] [Production Example (1) 13: Compound α-13] [ka] In step 1, compound α-13a (500.0 mg, 3.70 mmol) was placed in a dry 50 mL three-neck flask, hydrobromic acid (4 mL) was added, and bromine (621.0 mg, 3.88 mmol, 200 μL) was added dropwise to the flask at 15-20 °C. After the dropwise addition was complete, the reaction was stirred at 40 °C for 1 h, then the temperature was raised to 80 °C and stirring continued for 1 h. The reaction was complete as detected by LCMS. The mixture was cooled to 25-30 °C. tert-Butyl methyl ether (12 mL) was added to the reaction mixture. The mixture was stirred at 25-30 °C for 5 min, and then filtered under vacuum. The cake was washed with tert-butyl methyl ether (10 mL) and dried to obtain the product. The crude product α-13b (900.0 mg, 3.05 mmol, 82% yield, 91.5% purity, HBr) was used in the next step without purification. MS-ESI: [M+H] + =214.0

[0139] In step 2, a dry 50 mL three-neck flask was charged with acetone (2.40 mL), α-13b (183.0 mg, 620 μmol, HBr), and A1-1-1c (120.0 mg, 413 μmol). Diisopropylethylamine (53.3 mg, 413 μmol, 71.9 μL, 1.00 eq) was added dropwise at 20 °C. After the addition was complete, the mixture was stirred at 20 °C for 16 h. The reaction was confirmed to be complete by LCMS. Water (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (10 mL x 3). The mixture was washed with saturated brine (15 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by pre-HPLC (Waters*bridge 150 × 25 mm 10 μm column, mobile phase: [water (ammonium bicarbonate)-acetonitrile], B%: 43%-73%, 14 min). The mixture was lyophilized to give product α-13 (60.0 mg, 142 μmol, yield 34%, purity 95.3%). MS-ESI: [M+H] + =424.1

[0140] [Second Manufacturing Example (including an embodiment of the second technical solution)] [Production Example (2) 1: Compound A1-1-1] [ka] In step 1, diethyl carbonate (136.90 g, 1.16 mol) was dissolved in tetrahydrofuran (500 mL), the mixture was purged with nitrogen, and sodium hydride (23.18 g, 579.44 mmol) was added at 0 °C. The reaction was continued for 1 hour. Compound A1-1-1a (50 g, 289.72 mmol) was then added, and the reaction mixture was transferred to 55 °C and reacted for 8 hours. The reaction mixture was poured into 2 M aqueous hydrochloric acid (400 mL) and extracted with ethyl acetate. The extracted organic phase was washed twice with saturated brine (400 mL) and subjected to preparative column chromatography to obtain crude product A1-1-1b, which was used directly in the next step.

[0141] In step 2, the crude product A1-1-1b was dissolved in methanesulfonic acid (400 mL), resorcinol (45.01 g, 408.75 mmol) was added, and the mixture was allowed to react at 45 °C for 3 h to give a black viscous reaction mixture. TLC showed that the starting material was completely consumed, so the reaction mixture was slowly poured into ethanol (200 mL), and the resulting liquid was poured into water (500 mL). The mixture was extracted with ethyl acetate (300 mL × 3), and the combined organic phase was washed once with saturated brine (500 mL), dried over anhydrous sodium sulfate, and purified by column chromatography to give A1-1-1c (40.00 g, 137.61 mmol, 47.5% overall yield for the two steps). 1 H NMR (400 MHz, chloroform-d): 7.35-7.29 (m, 1H), 7.26-7.21 (m, 1H), 7.20-7.10 (m, 1H), 7.02-7.08 (m, 1H), 6.76-6.82 (m, 1H), 6.40-6.52 (m, 1H), 6.21 (s, 1H), 5.51 (s, 1H).

[0142] In step 3, A1-1-1d (13.32 g, 89.93 mmol), cuprous bromide (0.91 g, 6.36 mmol), and anhydrous tetrahydrofuran (120 mL) were added to a 250 mL three-neck flask protected with nitrogen, in that order. After complete dissolution, the temperature was cooled to -20 °C, and then ethylmagnesium bromide in tetrahydrofuran (50 mL, 2.0 M) was slowly added dropwise. After the addition was complete, the mixture was allowed to react at this temperature for 1 hour. The temperature was then slowly raised to 30 °C and the mixture was allowed to react for 2 hours. After complete reaction, the mixture was quenched with saturated aqueous ammonium chloride (100 mL), extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, and purified using a rapid separation column to obtain A1-1-1e (13.0 g, 72.96 mmol, 81% yield). MS-ESI:[MH] - =177.1

[0143] In step 4, A1-1-1e (13.0 g, 72.96 mmol), anhydrous potassium carbonate (20.17 g, 145.92 mmol), and N,N-dimethylformamide (50 mL) were added to a 100 mL three-neck flask in this order. The reaction mixture was heated to 60 °C, and iodomethane (20.71 g, 145.92 mmol) was slowly added dropwise. After the addition was complete, the mixture was allowed to react at that temperature for 6 hours. TLC monitoring was performed. After the starting materials had completely reacted, the reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, and then purified using a rapid separation column to obtain A1-1-1f (5.9 g, 30.70 mmol, 42% yield). 1H NMR (400 MHz, chloroform-d) δ 7.93 (dd, J = 7.7, 1.4 Hz, 1H), 7.59 (td, J = 7.5, 1.3 Hz, 1H), 7.51 (td, J = 7.6, 1.4 Hz, 1H), 7.36 (dd, J = 7.5, 1.4 Hz, 1H), 3.91 (s, 3H), 2.83 (q, J = 7.3 Hz, 2H), 1.25 (t, J = 7.3 Hz, 3H).

[0144] In step 5, A1-1-1f (5.9 g, 30.70 mmol) and dichloromethane (15 mL) were added to a 100 mL three-neck flask at room temperature, and hydrogen bromide (1.86 mL, 34.24 mmol) and bromine (4.38 mL, 85.60 mmol) were added dropwise in this order. The reaction was allowed to proceed at room temperature for 4 hours. After the reaction was complete, the reaction mixture was quenched with saturated aqueous sodium thiosulfate (100 mL) and extracted with dichloromethane (30 mL × 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, and then purified using a rapid separation column to obtain A1-1-1g (1.7 g, 6.27 mmol, 20% yield). 1 H NMR(400MHz,chloroform-d)δ 8.02(dd,J=8.1,1.3Hz,1H),7.65(td,J=7.5,1.4Hz,1H),7.55(ddt,J=8.7, 3.8,1.5Hz,2H),4.85(q,J=6.6Hz,1H),3.93(s,3H),2.00(d,J=6.6Hz,3H).

[0145] In step 6, A1-1-1g (1.7 g, 6.27 mmol) and acetone (5 mL) were added to a 100 mL three-neck flask at room temperature. Then, A1-1-1c (1.92 g, 6.61 mmol), tetrabutylammonium iodide (2.44 g, 6.61 mmol), and anhydrous potassium carbonate (1.83 g, 13.22 mmol) were added in this order. The mixture was stirred overnight at room temperature and monitored by TLC. After the raw materials had completely reacted, the reaction mixture was diluted with water (25 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The resulting mixture was then purified using a rapid separation column to obtain A1-1-1h (1.17 g, 2.43 mmol, 39% yield). MS-ESI: [M+H] + =481.2

[0146] In step 7, A1-1-1h (1.17 g, 2.43 mmol) and methanol (20 mL) were added to a 100 mL three-neck flask, and aqueous sodium hydroxide (20 mL, 0.5 M) was added. The mixture was allowed to react at the same temperature for 3 hours. After the reaction was complete, monitored by TLC, the reaction mixture was adjusted to pH 2-3 with dilute aqueous hydrochloric acid (1.0 M) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, and then purified using a rapid separation column to obtain compound A1-1-1i (290.0 mg, 0.62 mmol, 25% yield).

[0147] In step 8, compound A1-1-1i was separated by SFC to obtain A1-1-1. Apparatus: SFC-80 (Waters), separation column model: CHIRALPAK AD (30 × 250 mm 5 μm) (Daicel), separation conditions: ethanol (0.2% TFA), 75% CO2, flow rate: 45 mL / min. ESI-LCMS: m / z [M+H] + 467.0. 1H NMR(400MHz,DMSO-d6)δ 8.40(d,J=31.2Hz,1H),7.88-7.66(m,4H),7.63-7.51(m,1H),7.43(d,J=8.6Hz,1H),7.10(s,1H),6 .94-6.63(m,2H),6.29(d,J=6.4Hz,1H),5.12(dd,J=86.7,6.7Hz,1H),1.39(dd,J=40.3,6.2Hz,3H).

[0148] [Production Example (2) 2: Compound A2-1-1] [ka] Compound A1-1-1i was separated by SFC to obtain A2-1-1. Apparatus: SFC-80 (Waters), separation column model: CHIRALPAK AD (30 × 250 mm 5 μm) (Daicel), separation conditions: ethanol (0.2% TFA), 75% CO, flow rate: 45 mL / min.

[0149] [Production Example (2) 3: Compound A1-1-5] [ka] In step 1, palladium acetate (0.63 g, 2.82 mmol) and XantPhos (1.63 g, 2.82 mmol) were added to a dry three-neck flask and protected with nitrogen. A1-1-5a (20 g, 93.87 mmol), N,N-dimethylformamide (250 mL), and DCC (3.87 g, 18.77 mmol) were added, again protected with nitrogen. Formic acid (30.25 g, 657.09 mmol) and triethylamine (19.00 g, 26.02 mmol) were added and the mixture was heated at 110 °C for 12 h. TLC showed that the starting materials were almost completely reacted. Water (500 mL) and tert-butyl methyl ether (500 mL) were added, and the mixture was stirred to homogenize, then filtered through diatomaceous earth and separated. The aqueous phase was extracted three times with tert-butyl methyl ether (300 mL × 3), and the combined organic phases were washed with saturated aqueous sodium chloride solution (500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product A1-1-5b, which was used directly in the next step.

[0150] In step 2, the crude product A1-1-5b was dissolved in methanol (200 mL), and DMAP (5.14 g, 42.09 mmol), N,N-diisopropylethylamine (21.76 g, 168.36 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (24.21 g, 126.27 mmol) were added. The mixture was allowed to react at room temperature for 12 hours. TLC analysis showed that the starting material was almost completely reacted. After concentration, ethyl acetate (200 mL) and saturated aqueous sodium chloride (200 mL) were added, and the mixture was separated. The aqueous phase was extracted twice with ethyl acetate (100 mL × 2). The combined organic phases were washed first with 1 M aqueous hydrogen chloride (100 mL), then with saturated aqueous sodium chloride (200 mL), then with saturated aqueous sodium bicarbonate (200 mL), and finally with saturated aqueous sodium chloride (200 mL). The resulting organic phase was dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to give A1-1-5c (8.00 g, 41.62 mmol, total yield for two steps: 44%).

[0151] In step 3, A1-1-5c (8.00 g, 41.62 mmol) was dissolved in tetrahydrofuran (100 mL), pyridinium bromide perbromide (26.62 g, 83.24 mmol) was added, and the mixture was allowed to react at 45 °C for 3 hours. TLC showed that the starting material had almost completely reacted. After filtration and concentration, ethyl acetate (100 mL) and saturated aqueous sodium chloride solution (100 mL) were added and the mixture was separated. The aqueous phase was extracted twice with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give A1-1-5d (6.50 g, 23.98 mmol, 57% yield).

[0152] In step 4, A1-1-5d (6.5 g, 23.98 mmol), A1-1-1c (6.97 g, 23.98 mmol), and potassium carbonate (8.29 g, 59.95 mmol) were added to acetone (100 mL) and reacted overnight at room temperature. TLC showed that the starting materials had reacted almost completely. After concentration, ethyl acetate (100 mL) and water (100 mL) were added and the mixture was separated. The aqueous phase was extracted twice with ethyl acetate (100 mL × 2). The combined organic phases were washed with 1 M aqueous hydrogen chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give A1-1-5e (7.01 g, 14.58 mmol, 60% yield). 1 H NMR(400MHz,chloroform-d)δ 8.61(q,J=1.6Hz,1H),8.18(ddt,J=21.2,7.9,1.6Hz,2H),7.53(t,J=7.8Hz,1H),7.21-7.16(m,2H),7.11-7.00(m,1H),6.87(dd,J=8 .8,3.8Hz,1H),6.70(ddd,J=18.7,9.6,2.5Hz,2H),6.08(d,J=1.1Hz,1H),5.58(q,J=6.9Hz,1H),3.88(s,3H),1.70(d,J=6.9Hz,3H).

[0153] In step 5, A1-1-5e (3 g, 6.24 mmol) was dissolved in a mixture of methanol (50 mL) and tetrahydrofuran (100 mL). 2 M aqueous sodium hydroxide (50 mL) was added in an ice bath, and the mixture was allowed to react for 25 minutes. TLC showed complete reaction. 1 M hydrochloric acid (120 mL) was added, followed by extraction with ethyl acetate (200 mL). The aqueous phase was washed twice with ethyl acetate (150 mL × 2). The combined organic phases were washed with saturated sodium chloride (150 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give A1-1-5f (1.34 g, 2.87 mmol, 46% yield, 96.45% purity).

[0154] In step 6, compound A1-1-5f was separated by SFC to give A1-1-5. Apparatus: SFC-80 (Waters), separation column model: CHIRALPAK AD (30 × 250 mm 5 μm) (Daicel), separation conditions: ethanol (0.2% TFA), 75% CO, flow rate: 45 mL / min. 1 H NMR(400MHz,chloroform-d),8.81(s,1H),8.35(dd,J=26.9,7.8Hz,2H),7.68(t,J=7.8Hz,1H),7.33-7.28(m,2H),7.17-7.10( m,1H),6.97(dd,J=8.8,4.0Hz,1H),6.81(dd,J=11.2,5.2,2H),6.20(s,1H),5.65(q,J=6.8Hz,1H),1.82(d,J=6.8Hz,3H). MS(ES) [MH] - :C 25 H 16 ClFO6 theoretical value: 466.1, actual value: 465.0.

[0155] [Production Example (2) 4: Compound A2-1-5] [ka] Compound A1-1-5f was separated by SFC to obtain A2-1-5. Apparatus: SFC-80 (Waters), separation column model: CHIRALPAK AD (30 × 250 mm 5 μm) (Daicel), separation conditions: ethanol (0.2% FATFA), 75% CO, flow rate: 45 mL / min.

[0156] [Production Example (2) 5: Compound A1-1-6] [ka] A1-1-5 (100.0 mg, 214 μM) was dissolved in N,N-dimethylformamide (0.5 mL), and then the solution was adjusted to alkaline by adding aqueous sodium carbonate. The solution was then purified by reverse-phase medium-pressure chromatography (MeCN:HO) to give A1-1-6 (63.0 mg, 129 μM, 60%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.50(t,J=1.7Hz,1H),8.15(dt,J=7.6,1.4Hz,1H),8.01(dq,J=7.8,1.7Hz,1H),7.68(dt ,J=8.9,2.7Hz,1H),7.55(ddd,J=8.8,6.1,2.9Hz,1H),7.47(t,J=7.6Hz,1H),7.45-7.38 (m,1H),7.01(dd,J=4.6,2.4Hz,1H),6.94(dd,J=8.9,1.5Hz,1H),6.87(ddd,J=8.9,6.4, 2.4Hz,1H),6.29(d,J=1.4Hz,1H),6.27-6.16(m,1H),1.58(dd,J=6.7,1.2Hz,3H).MS(ES) [M+H] + :C 25 H 15 Free acid C of ClFO6Na 25 H 16 ClFO6 theoretical value: 466.1, actual value: 467.0.

[0157] [Production Example (2) 6: Compound A1-1-9] [ka] In step 1, A1-1-9a (2.0 g, 11.22 mmol) and dry N,N-dimethylformamide (30 mL) were added to a dry 100 mL three-neck flask in this order. After complete dissolution, iodomethane (4.78 g, 33.66 mmol) and sodium bicarbonate (2.83 g, 33.66 mmol) were added in this order. After all the raw materials were added, the temperature was slowly raised to 30 °C and the reaction was continued for 6 hours while maintaining the temperature. The reaction was monitored by TLC until the raw materials were completely reacted. After the reaction was completed, water (50 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with water (50 mL × 2) and then with saturated brine. The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. After concentration on a rotary evaporator, the product was purified using a rapid separation column to obtain A1-1-9b (2.0 g, 10.41 mmol, yield 92%).

[0158] In step 2, A1-1-9b (2.0 g, 10.41 mmol) and dry tetrahydrofuran (30 mL) were added to a dry 100 mL three-neck flask in this order, and after sufficient dissolution, 2-pyrrolidone (1.06 g, 12.49 mmol) and pyrrolidone hydrotribromide (5.09 g, 15.62 mmol) were added in this order. After all the raw materials were added, the temperature was slowly raised to 50°C, and the reaction was continued for 3 hours while maintaining the temperature. The reaction was monitored by TLC until the raw materials had completely reacted. After the reaction was completed, the reaction mixture was added dropwise to a saturated aqueous solution of disodium disulfite (20 mL) and stirred for 5 minutes. Then, water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, and purified using a rapid separation column to obtain A1-1-9c (2.10 g, 7.75 mmol, 74% yield).

[0159] In step 3, A1-1-9c (2.00 g, 7.38 mmol), A1-1-1c (2.13 g, 7.38 mmol), and dry acetone (30 mL) were added to a dry 100 mL three-neck flask in this order and thoroughly dissolved. After that, potassium carbonate (2.04 g, 14.76 mmol) and tetrabutylammonium iodide (2.73 g, 7.38 mmol) were added in this order. After all the raw materials were added, the temperature was slowly raised to 25°C, and the reaction was continued for 6 hours while maintaining the temperature. The reaction was monitored by TLC until the raw materials had completely reacted. After the reaction was completed, water (50 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated using a rotary evaporator, and purified using a rapid separation column to obtain A1-1-9d (2.14 g, 4.45 mmol, yield 60%).

[0160] In step 4, A1-1-9d (1.0 g, 2.08 mmol) and tetrahydrofuran (30 mL) were added to a dry 100 mL three-neck flask in this order. After complete dissolution, aqueous NaOH (2.0 M, 15 mL) was slowly added dropwise. Then, methanol (10 mL) was added as a cosolvent to the reaction mixture. After the entire mixture was added, the reaction was maintained at room temperature for 10 minutes, and the mixture was monitored by TLC until complete reaction. After completion of the reaction, the reaction mixture was acidified (pH 3-5) with dilute aqueous hydrochloric acid (1.0 M). The mixture was then extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, and purified using a rapid separation column to obtain compound A1-1-9e (380.0 mg, 0.81 mmol, 39% yield).

[0161] In step 5, compound A1-1-9e was separated by SFC to obtain A1-1-9. Apparatus: SFC-80 (Waters), separation column model: CHIRALPAK AD (30 × 250 mm 5 μm) (Daicel), separation conditions: ethanol (0.2% TFA), 75% CO, flow rate: 45 mL / min. MS-ESI: [M+H] +=467.2 1 H NMR(400MHz,DMSO-d6)δ 12.99(s,1H),7.94-7.86(m,2H),7.66-7.61(m,1H),7.57-7.33(m,4H),7.13(dd,J=8.2, 2.4Hz,1H),6.69(s,1H),6.33-6.28(m,1H),6.21(s,1H),4.61(m,1H),1.34-1.22(m,3H).

[0162] [Production Example (2) 7: Compound A2-1-9] [ka] Compound A1-1-9e was separated by SFC to obtain A2-1-9. Apparatus: SFC-80 (Waters), separation column model: CHIRALPAK AD (30 × 250 mm 5 μm) (Daicel), separation conditions: ethanol (0.2% FATFA), 75% CO, flow rate: 45 mL / min.

[0163] [Production Example (2) 8: Compound A1-4-5] [ka] In step 1, A1-4-5a (13.0 g, 64.35 mmol) and dry dichloromethane (130 mL) were added to a dry 500 mL three-neck flask in this order and thoroughly dissolved. After that, methoxy(methyl)amine hydrochloride (6.28 g, 64.35 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (29.36 g, 77.22 mmol), and triethylamine (16.28 g, 160.88 mmol) were added in this order. After all the raw materials were added, the reaction was carried out at room temperature for 16 hours and monitored by TLC until the raw materials had completely reacted. After the reaction was completed, water (150 mL) was added to the reaction mixture, which was then extracted with dichloromethane (200 mL × 3). The combined organic phases were washed with purified water (300 mL). After the washing was complete, the organic phase was washed with saturated brine (300 mL). The resulting mixture was then dried over anhydrous sodium sulfate and concentrated using a rotary evaporator. After that, the resulting mixture was purified using a rapid separation column to obtain A1-4-5b (14.3 g, 58.36 mmol, 90% yield).

[0164] In step 2, A1-4-5b (14.00 g, 57.13 mmol) and dry tetrahydrofuran (150 mL) were added to a dry 500 mL three-neck flask in that order, and after sufficient dissolution, the flask was purged with N2 three times and cooled to -15 °C. Ethyl magnesium bromide (11.2 mL, 85.70 mmol, 2.0 M tetrahydrofuran) was slowly added dropwise, and once all the starting materials had been added, the mixture was slowly warmed to room temperature and reacted for 3 hours, and monitored by TLC until the starting materials had completely reacted. After the reaction was completed, the reaction mixture was added dropwise to saturated aqueous ammonium chloride solution (50 mL) and stirred for 5 minutes. Then, water (50 mL) was added and extracted with ethyl acetate (150 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, and purified using a rapid separation column to obtain A1-4-5c (8.66 g, 40.46 mmol, 70% yield).

[0165] In step 3, A1-4-5c (8.50 g, 39.71 mmol), Xantphos (4.60 g, 7.94 mmol), DCC (16.39 g, 79.42 mmol), and Pb(OAc) (1.78 g, 7.94 mmol) were added to a dry 250 mL three-neck flask in this order. Next, dry N,N-dimethylformamide (150 mL) was added and the reaction mixture was purged with nitrogen three times. Triethylamine (16.5 mL, 119.13 mmol) and formic acid (3 mL, 79.42 mmol) were added dropwise to the reaction mixture in this order. Once all the starting materials were added, the temperature was slowly raised to 100 °C and maintained at this temperature for 6 h. The reaction was monitored by TLC until the starting materials were completely reacted. After the reaction was completed, water (100 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, and purified using a rapid separation column to obtain A1-4-5d (5.13 g, 29.64 mmol, 72% yield), which was used directly in the next step.

[0166] In step 4, A1-4-5d (5.00 g, 27.91 mmol) and dry N,N-dimethylformamide (80 mL) were added to a dry 250 mL three-neck flask in this order, and after sufficient dissolution, iodomethane (5.94 g, 41.87 mmol) and potassium carbonate (7.71 g, 55.82 mmol) were added in this order. After all the raw materials were added, the temperature was slowly raised to 25°C, and the reaction was continued for 6 hours while maintaining the temperature. The reaction was monitored by TLC until the raw materials had completely reacted. After the reaction was completed, water (80 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (100 mL × 3). The combined organic phases were then washed with purified water (100 mL × 2). After the washing was complete, the organic phase was washed with saturated brine (200 mL). The resulting mixture was then dried over anhydrous sodium sulfate and concentrated using a rotary evaporator. The resulting mixture was then purified using a rapid separation column to obtain A1-4-5e (1.47 g, 7.61 mmol, 27% yield).

[0167] In step 5, A1-4-5e (1.40 g, 7.25 mmol) and dry tetrahydrofuran (30 mL) were added in this order to a dry 100 mL three-neck flask, and after sufficient dissolution, 2-pyrrolidone (0.74 g, 8.70 mmol) and pyrrolidone hydrotribromide (3.54 g, 10.88 mmol) were added in this order. After all the raw materials were added, the temperature was slowly raised to 50°C, and the reaction was continued for 3 hours while maintaining the temperature. The reaction was monitored by TLC until the raw materials had completely reacted. After the reaction was completed, the reaction mixture was added dropwise to a saturated aqueous solution of disodium disulfite (20 mL) and stirred for 5 minutes. Then, water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated using a rotary evaporator, and purified using a rapid separation column to obtain A1-4-5f (1.49 g, 5.47 mmol, 76% yield).

[0168] In step 6, A1-4-5f (1.40 g, 5.15 mmol), A1-1-1c (1.49 g, 5.15 mmol), and dry acetone (20 mL) were added to a dry 100 mL three-neck flask in this order and thoroughly dissolved. After that, potassium carbonate (1.42 g, 10.30 mmol) and tetrabutylammonium iodide (1.90 g, 5.15 mmol) were added in this order. After all the raw materials were added, the temperature was slowly raised to 25 °C, and the reaction was continued for 6 hours while maintaining the temperature. The reaction was monitored by TLC until the raw materials had completely reacted. After the reaction was completed, the reaction mixture was washed with water (30 mL) and then extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated using a rotary evaporator, and then purified using a rapid separation column to obtain A1-4-5g (1.35 g, 2.80 mmol, yield 54%).

[0169] In step 7, Al-4-5g (1.35 g, 2.80 mmol) and tetrahydrofuran (30 mL) were added to a dry 100 mL three-neck flask in this order. After dissolving, lithium hydroxide solution (1.0 M, 15 mL) was slowly added dropwise. Methanol (10 mL) was then added as a cosolvent to the reaction mixture. After the entire mixture was added, the reaction was maintained at room temperature for 2 hours and monitored by TLC until the reaction was complete. After the reaction was complete, the reaction mixture was acidified with formic acid (pH 4-5), extracted with ethyl acetate (50 mL x 3), and the combined organic phases were washed with saturated brine (100 mL). The organic phase was then dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, and purified using a rapid separation column to obtain compound Al-4-5h (730 mg, 1.56 mmol, 55% yield). MS-ESI: [M+H] + =468.0

[0170] In step 8, compound A1-4-5h was separated by SFC to give A1-4-5. The separation column was a CHIRALPAK AD (30 × 250 mm, 5 μm) (Daicel) with ethanol (0.2% TFA) and 75% CO2 at a flow rate of 45 mL / min.

[0171] [Production Example (2) 9: Compound A2-4-5] [ka] Compound A1-4-5h was separated by SFC to give A2-4-5. Apparatus: SFC-80 (Waters), separation column model: CHIRALPAK AD (30 × 250 mm 5 μm) (Daicel), separation conditions: ethanol (0.2% FATFA), 75% CO, flow rate: 45 mL / min.

[0172] [Third Manufacturing Example (including the embodiment of the third technical solution)] [Production Example (3) 1: Compound A-1-8-1-1] [ka] In step 1, in a dry 100 mL three-neck flask, compound A-1-8-1-1a (5.98 g, 26.08 mmol) was dissolved in dichloromethane (20 mL), and then N,O-dimethylhydroxyamine hydrochloride (3.03 g, 31.30 mmol), triethylamine (7.5 mL, 57.34 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (11.89 g, 31.30 mmol) were added in this order. The reaction mixture was reacted at room temperature for 1 hour and monitored by TLC until the raw materials were completely reacted. 40 mL of water was added to quench the reaction, and then extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated by rotary evaporator, and then purified by rapid separation column to obtain the concentrated organic phase, which was then purified by normal phase purification (PE:EA = 5:1, R f =0.4) to obtain the target product A-1-8-1-1b (6.50 g, 23.89 mmol, yield 91.67%) as a colorless oil.

[0173] In step 2, in a dry 100 mL three-neck flask, compound A-1-8-1-1b (6.50 g, 23.89 mmol) was dissolved in tetrahydrofuran (30 mL) and protected with nitrogen. Then, ethyl magnesium bromide (28.66 mL, 28.66 mmol) was added dropwise. Then, the reaction mixture was reacted at room temperature for 16 hours. The reaction mixture was monitored by TLC. When the reaction was complete, 20 mL of saturated ammonium chloride was added to quench the reaction. Then, 50 mL of ethyl acetate was added three times to extract the organic phase. Then, the organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, and further spin-dried. The organic phase was purified by normal phase purification (PE:EA=5:1, R f =0.6) to obtain the target product A-1-8-1-1c (5.00 g, 20.72 mmol, yield 86.84%) as a colorless oil.

[0174] In step 3, in a dry 100 mL three-neck flask, compound A-1-8-1-1c (1 g, 4.15 mmol) was dissolved in tetrahydrofuran (30 mL), and then pyridinium bromide perbromide (1.99 g, 6.22 mmol) was added. The reaction mixture was then reacted at room temperature for 16 hours, and the reaction mixture was spotted (PE:EA=10:1, R f =0.7), a new spot was formed and it was detected that the raw material still remained, so HO (20 mL) was added to quench the reaction, and then ethyl acetate (20 mL × 3) was added for extraction, and then the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and further spin-dried to obtain the desired product A-1-8-1-1d as a yellow oil, which was directly used in the next step.

[0175] In step 4, in a dry 100 mL three-neck flask, the crude product of compound A-1-8-1-1d (1.33 g, 4.15 mmol) was dissolved in acetone (30 mL), and then A1-1-1c (0.60 g, 2.07 mmol) and potassium carbonate (1.14 g, 8.30 mmol) were added. The reaction mixture was then reacted at room temperature for 16 hours, and the reaction mixture was spotted (PE:EA=3:1, R f =0.5), a new spot was formed, and it was detected that the raw material still remained. 20 mL of water was added to quench the reaction, and then ethyl acetate (20 mL × 3) was added for extraction. The organic phase was then washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was subjected to normal phase purification and spin-dried to obtain the desired product A-1-8-1-1e (0.43 g, 0.81 mmol, 19% yield) as a yellow oil.

[0176] In step 5, in a dry 100 mL three-neck flask, compound A-1-8-1-1e (0.43 g, 0.81 mmol) was dissolved in a hydrochloric acid-ethyl acetate solution (3 M, 10 mL). The reaction mixture was then reacted at room temperature for 1 hour. The reaction mixture was spotted, and when a new spot was formed, the raw materials were detected as having completely reacted. 40 mL of saturated sodium bicarbonate was added to quench the reaction, and ethyl acetate (20 mL × 3) was added for extraction. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, and purified using normal phase chromatography (DCM:MeOH = 10:1, R f =0.5), and spin-dried to obtain the desired product A-1-8-1-1 (0.29 g, 0.67 mmol, yield 83.26%, purity 95.33%) as a white solid. MS-ESI: [M+H] + =430.1 1 H NMR (400 MHz, chloroform-d) δ 7.32 (ddd, J = 8.4, 5.5, 3.0 Hz, 2H), 7.17 (t, J = 8.2 Hz, 1H), 7.02 (d, J = 6.9 Hz, 1H), 6.95-6.89 (m, 1H), 6.87-6.77 (m, 1H), 6.23 (d, J = 2.4 Hz, 1H), 5.02-4.89 (m, 1H), 3.73 (dt, J = 17.0, 8.5 Hz, 1H), 3. 57(d,J=13.2Hz,1H),3.41(t,J=13.5Hz,1H),3.00(dd,J=20.6,11.0Hz,1H),2.89(d,J=12.9Hz,1 H),2.31(s,1H),2.02-1.86(m,2H),1.59(dd,J=13.5,6.8Hz,3H),1.27(dd,J=14.8,10.8Hz,2H).

[0177] [Production Example (3) 2: Compound A-1-10-1-30] [ka] In step 1, compound A-1-10-1-30a (4 g, 15.08 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (11.47 g, 30.16 mmol) were dissolved in N,N-dimethylformamide (100 mL) in a dry 500 mL three-neck flask. After stirring at room temperature for 5 minutes, triethylamine (4.58 g, 45.24 mmol) and methoxy(methyl)amine hydrochloride (1.38 g, 22.62 mmol) were added in that order. The mixture was stirred for 16 hours, and TLC showed complete reaction. Ethyl acetate (100 mL) was added, followed by washing and extraction three times with 50 mL of 5% aqueous hydrochloric acid and 100 mL of saturated brine. The organic phase was collected, dried, and spun to give the desired product A-1-10-1-30b (4.50 g, 14.59 mmol, 96.79% yield), which was used directly in the next step.

[0178] In step 2, A-1-10-1-30b (4.5 g, 14.59 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL) in a dry 500 mL three-neck flask. The flask was purged with nitrogen at 0 °C and a solution of ethylmagnesium bromide in tetrahydrofuran (3.89 g, 29.18 mmol) was added. After the dropwise addition was complete, the mixture was cooled to room temperature and reacted for 2-3 hours. Acetic acid (5 mL) was added, followed by water (10 mL). The mixture was stirred for 5 minutes, then concentrated to dryness. Dry loading onto silica gel and column purification (PE:EA = 3:1) yielded the desired product as a pale yellow oil. H NMR (LJH-97-P1) confirmed that the pale yellow oil was the desired product A-1-10-1-30c (2.2 g, 7.93 mmol, 54.36% yield).

[0179] In step 3, A-1-10-1-30c (2.2 g, 7.93 mmol) was dissolved in tetrahydrofuran (40 mL) in a dry 100 mL three-neck flask, and pyridinium bromide perbromide (5.07 g, 15.86 mmol) was added. The reaction was allowed to proceed at 45 °C for 16 hours, and TLC (PE:EA = 3:1, R f= 0.49) indicates partial reaction. Ethyl acetate (40 mL) was added, washed twice with water (40 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness to give crude product A-1-10-1-30d (1.00 g, 2.81 mmol, 35.39% yield), which was used directly in the next step.

[0180] In step 4, in a dry 100 mL three-neck flask, compounds A-1-10-1-30d (1.00 g, 2.81 mmol) and A1-1-1c (0.82 g, 2.81 mmol) were dissolved in acetone (50 mL), and then potassium carbonate (0.78 g, 5.62 mmol) was added. The reaction mixture was allowed to react at room temperature for 24 hours to obtain an ochre suspension. The reaction mixture was spotted (PE:EA = 1:1, R f =0.38), complete reaction was detected, the reaction solution was sucked dry, 50 mL of ethyl acetate and 50 mL of water were added to the residue, extracted, and the organic phase was collected and dried to obtain a crude product, which was then subjected to column purification twice to obtain the target product A-1-10-1-30e (1.20 g, 2.12 mmol, yield 75%) as a pale yellow solid.

[0181] In step 5, in a dry 100 mL three-neck flask, compound A-1-10-1-30e (0.6 g, 1.06 mmol) was dissolved in methanol (20 mL), and 350.0 mg of palladium-carbon water-wet (5%) was added. Then, the atmosphere was replaced with hydrogen, and the reaction mixture was reacted at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was spotted, and if a new spot was formed, the remaining raw materials were detected, and the impurity spots increased, the reaction was stopped, filtered, and purified by normal phase purification (DCM:MeOH=10:1, R f =0.5) and spin-dried to give the desired product A-1-10-1-30 (0.15 g, 0.35 mmol, 32.83% yield) as a white solid. MS-ESI: [M+H] + =432.1 1H NMR(400MHz,chloroform-d)δ=7.36-7.29(m,2H),7.16(s,1H),6.98(d,J=8.8Hz,1H) ,6.85-6.72(m,2H),6.21(s,1H),5.39(ddd,J=17.5,11.2,7.3Hz,1H),4.23(t,J= 7.2Hz,1H),4.03(t,J=11.1Hz,1H),3.79-3.64(m,1H),3.26(dd,J=28.4,12.3Hz ,1H),3.06-2.86(m,2H),2.79(t,J=11.3Hz,1H),1.77(s,1H),1.67-1.58(m,3H).

[0182] [Production Example (3) 3: Compound A-1-2-1-1] [ka] In step 1, palladium acetate (0.63 g, 2.82 mmol) and the ligand 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.63 g, 2.82 mmol) were added to a dry 500 mL three-neck flask and purged with nitrogen. tert-Butanol (20.87 g, 281.6 mmol), A-1-2-1a (30.00 g, 140.80 mmol), and triethylamine (28.50 g, 281.6 mmol) were added, the mixture was clarified with toluene (300 mL), and purged with nitrogen. After all the contents were added, a mixture of formic acid (12.96 g, 281.6 mmol) and acetic anhydride (28.75 g, 281.6 mmol) was stirred at 30° C. for 1.5 hours and then added to the reaction flask. After the dropwise addition was completed, the temperature was raised to 80°C and the reaction was continued for 4 hours. After the reaction was completed, the insoluble matter in the reaction solution was filtered, and the reaction solution was washed with 300 mL of distilled water and 300 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to give an ochre crude product. The crude product was slurried with PE and dried to give the orange product A-1-2-1b (20.00 g, 112.24 mmol, 79.72% yield). MS-ESI:[MH] - =177.1

[0183] In step 2, A-1-2-1b (20.00 g, 112.24 mmol), di-tert-butyl dicarbonate (49.00 g, 224.48 mmol), and 4-dimethylaminopyridine (6.86 g, 56.12 mmol) were mixed in a dry 500 mL three-neck flask and dissolved in tert-butanol (200 mL). The mixture was stirred at room temperature for 12 hours, and potassium carbonate (62.06 g, 448.96 mmol) was dissolved in water (50 mL) and poured into the reaction mixture. The mixture was stirred for 1 hour, and the progress of the reaction was monitored by TLC. The mixture was extracted with ethyl acetate (100 mL × 3), and after the extraction was completed, it was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and subjected to chromatography (PE:EA = 1-20%) to obtain a colorless oily liquid A-1-2-1c (21.66 g, 92.45 mmol, 82% yield). 1 H NMR(400MHz,chloroform-d)δ 8.52(d,J=1.9Hz,1H),8.12(ddt,J=16.4,7.8,1.5Hz,2H),7.50(t,J=7.7Hz,1H),3.02(q,J=7.2Hz,2H),1.60(s,9H),1.22(t,J=7.2Hz,3H).

[0184] In step 3, A-1-2-1c (23.50 g, 100.30 mmol) was dissolved in 200 mL of tetrahydrofuran in a dry 500 mL single-neck flask. Pyridinium bromide perbromide (38.49 g, 120.00 mmol) was added in portions at 0 °C. After addition, the mixture was cooled to room temperature and stirred for 5 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was filtered, the filtrate was spin-dried, and 200 mL of ethyl acetate was added. The mixture was washed first with water (100 mL x 2), then with 100 mL of saturated sodium bicarbonate, and then with 100 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate, spin-dried, and purified by chromatography (PE:EA = 10:1) to give A-1-2-1d (30.10 g, 96.11 mmol, 95% yield) as a yellow oil.

[0185] In step 4, diethyl carbonate (17.11 g, 144.80 mmol) was dissolved in tetrahydrofuran (50 mL) in a dry 100 mL three-neck flask and purged with nitrogen. The reaction apparatus was placed in a low-temperature reaction vessel and cooled to 0 °C. Sodium hydride (2.90 g, 72.40 mmol) was added in several portions and reacted for 1 hour. Next, A-1-2-1e (5.00 g, 36.20 mmol) was added to the flask. The temperature was then slowly raised to room temperature, and the reaction time was 2 hours (preferably 2 to 4 hours). When TLC showed the reaction was complete, the mixture was quenched with 1 M hydrochloric acid solution at 0 °C until the pH reached 1, and the temperature was controlled not to exceed 10 °C. The reaction mixture was extracted with ethyl acetate (100 mL × 3), the layers were separated, and the organic phases were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and rotary evaporated to give the crude intermediate A-1-2-1f (4.20 g, 19.98 mmol, 55.2% yield).

[0186] In step 5, A-1-2-1f (4.20 g, 19.98 mmol) and resorcinol (2.2 g, 19.98 mmol) were dissolved in methanesulfonic acid (30 mL) in a dry 100 mL three-neck flask, and the mixture was heated to 50 °C and reacted for 4 hours (preferably 4 to 8 hours). When LCMS showed the reaction was complete, the reaction mixture was slowly added to ethanol (100 mL) to control the quench temperature. The reaction mixture was then added to water (100 mL), extracted with ethyl acetate (200 mL x 3), and the layers were separated. The combined organic phases were washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, and rotary evaporated to give the crude intermediate A-1-2-1g (3.0 g, 11.71 mmol, 59% yield). MS-ESI:[MH] - =255.1

[0187] In step 6, A-1-2-1g (1.64 g, 6.39 mmol), A-1-2-1d (2.0 g, 6.39 mmol), potassium carbonate (1.77 g, 12.78 mmol), and tetrabutylammonium iodide (2.36 g, 6.39 mmol) were added to a dry 100 mL three-neck flask in this order and dissolved in acetone (30 mL). The mixture was stirred at room temperature and reacted for 8 hours (preferably 8 to 12 hours). LCMS showed the reaction was complete. The insoluble matter was filtered, the solvent was removed by spin drying, water (30 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1) to give intermediate A-1-2-1h (0.62 g, 1.27 mmol, 19.9% ​​yield). MS-ESI:[MH] - =487.2

[0188] In step 7, A-1-2-1h (0.62 g, 1.27 mmol) was dissolved in dichloromethane (10 mL) in a dry 100 mL three-neck flask, trifluoroacetic acid (10 mL) was added, and the mixture was stirred and reacted for 4 hours (preferably 4-8 hours). LCMS showed the reaction was complete, and the solvent was removed by spin drying. The product A-1-2-1 was purified by silica gel column chromatography (PE:EA = 2:1) to give the product A-1-2-1 (395.9 mg, 0.92 mmol, 72% yield). MS-ESI:[MH] - =431.1 1H NMR (400 MHz, chloroform-d) δ 8.80(t,J=1.7Hz,1H),8.36(dt,J=7.7,1.5Hz,1H),8.30(dt,J=7.9,1.5Hz,1H) ,7.65(t,J=7.8Hz,1H),7.49(dddd,J=8.6,7.0,5.1,2.2Hz,1H),7.30(ddd,J=8 .3,6.8,1.5Hz,2H),7.21(dd,J=9.8,8.3Hz,1H),7.15(dd,J=9.1,2.4Hz,1H),6 .81(d,J=7.9Hz,2H),6.25(s,1H),5.63(q,J=6.8Hz,1H),1.80(d,J=6.9Hz,3H).

[0189] [Production Example (3) 4: Compound A-1-2-1-2] [ka] In step 1, diethyl carbonate (15.28 g, 129.36 mmol) was added to a dry 100 mL three-neck flask, and tetrahydrofuran (50 mL) was added to dissolve the mixture. The mixture was then purged with nitrogen. The reaction apparatus was placed in a low-temperature reaction vessel and cooled to 0 °C. Sodium hydride (2.59 g, 64.68 mmol) was added in several portions and allowed to react for 1 hour. Next, A-1-2-1-2a (5.00 g, 32.34 mmol) was added to the flask. The temperature was then slowly raised to room temperature, and the reaction time was 2 hours (preferably 2 to 4 hours). When TLC showed the reaction was complete, the mixture was quenched with 1 M hydrochloric acid solution at 0 °C until the pH reached 1. The temperature was controlled so that the temperature did not exceed 10 °C. The reaction mixture was extracted with ethyl acetate (100 mL × 3), the layers were separated, and the organic phases were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and rotary evaporated to give the crude intermediate A-1-2-1-2b (5.60 g, 24.71 mmol, 77.4% yield). 1H NMR(400MHz,DMSO-d6)δ 7.78(d,J=7.7Hz,1H),7.55(d,J=4.3Hz,2H),7.47(dt,J=8.2,4.0Hz,1H),4.14(s,2H),4.09(dd,J=7.1,2.7Hz,2H),1.14(t,J=7.1Hz,3H).

[0190] In step 2, A-1-2-1-2b (5.60 g, 24.71 mmol) and resorcinol (2.72 g, 24.71 mmol) were dissolved in methanesulfonic acid (30 mL) in a dry 100 mL three-neck flask, and the mixture was heated to 50 °C and reacted for 4 hours (preferably 4 to 8 hours). When LCMS showed the reaction was complete, the reaction mixture was slowly added to ethanol (100 mL) to control the quench temperature. The reaction mixture was then added to water (100 mL), extracted with ethyl acetate (200 mL x 3), and the layers were separated. The combined organic phases were washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, and rotary evaporated to give the crude intermediate A-1-2-1-2c (6.20 g, 22.74 mmol, 78.2% yield). MS-ESI:[MH] - =271.0

[0191] In step 3, A-1-2-1-2c (1.74 g, 6.39 mmol), tert-butyl 3-(2-bromopropionyl)benzoate (2.00 g, 6.39 mmol), potassium carbonate (1.77 g, 12.78 mmol), and tetrabutylammonium iodide (2.36 g, 6.39 mmol) were added to a dry 100 mL three-neck flask in this order, dissolved in acetone (30 mL), and stirred at room temperature for 8 hours (preferably 8 to 12 hours) to react. LCMS showed that the reaction was complete, and the insoluble matter was filtered off, the solvent was removed by spin drying, water (30 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3), and the layers were separated. The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain intermediate A-1-2-1-2d (0.90 g, 1.78 mmol, yield 27.9%). MS-ESI:[MH] - =503.1

[0192] In step 4, A-1-2-1-2d (0.90 g, 1.78 mmol) was dissolved in dichloromethane (10 mL) in a dry 100 mL three-neck flask, trifluoroacetic acid (10 mL) was added, and the mixture was stirred and reacted for 4 hours (preferably 4 to 8 hours). LCMS showed the reaction was complete, and the solvent was removed by spin drying. The product was purified by silica gel column chromatography (PE:EA = 2:1) to give product A-1-2-1-2 (113 mg, 0.25 mmol, 14% yield). MS-ESI:[MH] - =447.2 1 H NMR (400 MHz, chloroform-d) δ 8.79(q,J=1.8Hz,1H),8.36(dq,J=7.7,1.3Hz,1H),8.29(dt,J=8.0,1.5Hz, 1H),7.65(ddd,J=8.4,7.6,1.1Hz,1H),7.52(dt,J=7.9,1.5Hz,1H),7.46-7. 32(m,2H),7.29-7.20(m,1H),6.97(dd,J=8.8,4.0Hz,1H),6.86-6.68(m,2H ),6.20(d,J=1.1Hz,1H),5.63(dd,J=7.0,1.1Hz,1H),1.79(d,J=6.9Hz,3H).

[0193] [Production Example (3) 5: Compound A-1-2-6-1] [ka] In step 1, compound A-1-2-6-1a (2.50 g, 16.01 mmol) and resorcinol (1.94 g, 17.61 mmol) were weighed into a dry 100 mL three-neck flask and then dissolved in methanesulfonic acid (20 mL). The reaction mixture was then heated at 50 °C for 3 hours to obtain a black reaction mixture. After TLC analysis showed the starting materials were completely reacted, the reaction mixture was cooled to room temperature, 30 mL of ethanol was added, and solid sodium bicarbonate was added to adjust the pH to 6-7. 200 mL of water was added, followed by extraction with ethyl acetate (100 mL). The organic phase was then collected, dried, and concentrated. Column purification (PE:EA = 3:1) was performed to obtain the desired product A-1-2-6-1b (3.00 g, 14.84 mmol, 92.68% yield) as a yellow oil, which was used in the next step.

[0194] In step 2, compound A-1-2-6-1b (3.00 g, 14.84 mmol), A-1-2-1-1d (5.58 g, 17.81 mmol), and potassium carbonate (5.13 g, 37.1 mmol) were dissolved in acetone (30 mL) in a dry 100 mL three-neck flask. The reaction mixture was then allowed to react at room temperature to give a yellow suspension. When TLC showed the formation of a new spot and the starting materials had completely reacted, the reaction mixture was worked up by pouring the reaction mixture into ethyl acetate (50 mL), washing with saturated brine three times, collecting the organic phase, drying, and concentrating it. Column purification (PE:EA = 1:1) afforded the desired product A-1-2-6-1c (1.5 g, 3.45 mmol, 23.27% yield) as a yellow solid, which was used directly in the next step.

[0195] In step 3, compound A-1-2-6-1c (1.50 g, 3.45 mmol) was dissolved in dichloromethane (20 mL) in a dry 100 mL three-neck flask. Trifluoroacetic acid (0.79 g, 6.90 mmol) was then added and the reaction mixture was allowed to react at room temperature for 2 hours to yield a clear yellow liquid. Complete reaction of the starting materials was confirmed by spotting using TLC. 50 mL of ethyl acetate and 50 mL of water were added to the reaction mixture. The pH was then adjusted to 4-5 with solid sodium bicarbonate. The reaction mixture was extracted with ethyl acetate (40 mL x 2). The organic phases were collected, combined, dried over anhydrous sodium sulfate, and then spin-dried to yield the crude product as a dark yellow oil. The compound was purified by adding 50 mL of ethyl acetate to the crude product and dissolving it. Then, 25 mL of petroleum ether was slowly added and stirred continuously for 1 hour to obtain a yellow suspension. The mixture was filtered to obtain a pale yellow solid. The solid was collected, added with 50 mL of ethyl acetate, and refluxed for 3 hours to completely dissolve it. The solid was then concentrated and dry-loaded for column purification (PE:EA = 2:1) to obtain the target product. The target product was added with 2.5 mL of acetonitrile and 25 mL of water and lyophilized to obtain the target product A-1-2-6-1 (265 mg, 0.70 mmol, purity 99.26%, yield 20.2%) as a white solid. MS-ESI:[MH] - =377.1 1 H NMR(400MHz,DMSO-d6)δ 8.55(s,1H),8.31(d,J=8.0Hz,1H),8.23(d,J=7.8Hz,1H),7.97(d,J=8.8Hz,1H),7.71(t,J=7.8Hz,1H),6.98(dt,J=6.0,2.4 Hz,2H),6.27(q,J=6.7Hz,1H),5.89(s,1H),2.29-2.18(m,1H),1.59(d,J=6.7Hz,3H),1.11-1.04(m,2H),0.90-0.82(m,2H).

[0196] [Production Example (3) 6: Compound A-1-2-1-8] [ka] In step 1, diethyl carbonate (15.73 g, 133.20 mmol) was added to a dry 100 mL three-neck flask, and tetrahydrofuran (50 mL) was added to dissolve the mixture. The mixture was then purged with nitrogen. The reaction apparatus was placed in a low-temperature reaction vessel and cooled to 0 °C. Sodium hydride (2.59 g, 66.60 mmol) was added in several portions and reacted for 1 hour. Next, A-1-2-1-8a (5.00 g, 33.30 mmol) was added to the flask. The temperature was then slowly raised to room temperature, and the reaction time was 2 hours (preferably 2 to 4 hours). When TLC showed the reaction was complete, the mixture was quenched with 1 M hydrochloric acid solution at 0 °C until the pH reached 1. The temperature was controlled so that the temperature did not exceed 10 °C. The reaction mixture was extracted with ethyl acetate (100 mL × 3), the layers were separated, and the organic phases were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and rotary evaporated to give the crude intermediate A-1-2-1-8b (7.0 g, 22.05 mmol, yield 94.60%). MS-ESI: [M+H] + =223.2

[0197] In step 2, A-1-2-1-8b (7.00 g, 22.05 mmol) and resorcinol (2.43 g, 22.05 mmol) were dissolved in methanesulfonic acid (30 mL) in a dry 100 mL three-neck flask, and the mixture was heated to 50 °C and reacted for 4 hours (preferably 4 to 8 hours). When LCMS showed the reaction was complete, the reaction mixture was slowly added to ethanol (100 mL) to control the quench temperature. The reaction mixture was then added to water (100 mL), extracted with ethyl acetate (200 mL x 3), and the layers were separated. The combined organic phases were washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, and rotary evaporated to give the crude intermediate A-1-2-1-8c (5.50 g, 20.50 mmol, 79.00% yield). MS-ESI:[MH] - =267.0

[0198] In step 3, A-1-2-1-8c (1.54 g, 5.75 mmol), A-1-2-1-1d (2.00 g, 6.39 mmol), potassium carbonate (1.77 g, 12.78 mmol), and tetrabutylammonium iodide (2.36 g, 6.39 mmol) were added to a dry 100 mL three-neck flask in this order, dissolved in acetone (30 mL), and stirred at room temperature for 8 hours (preferably 8 to 12 hours) to react. LCMS showed that the reaction was complete, and the insoluble matter was filtered off, the solvent was removed by spin drying, water (30 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3), and the layers were separated. The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain intermediate A-1-2-1-8d (1.00 g, 2.00 mmol, yield 31.29%). MS-ESI:[M- t Bu] - =445.2

[0199] In step 4, A-1-2-1-8d (1.00 g, 2.00 mmol) was dissolved in dichloromethane (10 mL) in a dry 100 mL three-neck flask, trifluoroacetic acid (10 mL) was added, and the mixture was stirred and reacted for 4 hours (preferably 4 to 8 hours). LCMS showed the reaction was complete, and the solvent was removed by spin drying. The product was purified by silica gel column chromatography (PE:EA = 2:1) to give product A-1-2-1-8 (329.5 mg, 0.74 mmol, 36.80% yield, 99.16% purity). MS-ESI:[MH] - =443.1 1H NMR(400MHz,chloroform-d)δ 8.80(t,J=1.8Hz,1H),8.36(dt,J=7.8,1.4Hz,1H),8.29(dt,J=7.9,1.5Hz,1H),7.64(t,J=7.8Hz,1H),7.45(ddd,J=8.4,7.4,1.8Hz,1H ),7.18(dd,J=7.5,1.8Hz,1H),7.10-6.96(m,3H),6.76(s,2H),6.20(s,1H),5.62(d,J=8.0Hz,1H),3.73(s,3H),1.79(d,J=6.8Hz,3H).

[0200] [Production Example (3) 7: Compound A-1-2-1-9] [ka] In step 1, diethyl carbonate (14.39 g, 121.80 mmol) was added to a dry 100 mL three-neck flask, and tetrahydrofuran (50 mL) was added to dissolve the mixture. The flask was then purged with nitrogen. The reaction apparatus was placed in a low-temperature reaction vessel and cooled to 0 °C. Sodium hydride (2.44 g, 60.90 mmol) was added in several portions and allowed to react for 1 hour. Next, A-1-2-1-9a (5.00 g, 30.45 mmol) was added to the flask. The temperature was then slowly raised to room temperature, and the reaction time was 2 hours (preferably 2 to 4 hours). When TLC showed the reaction was complete, the mixture was quenched with 1 M hydrochloric acid solution at 0 °C until the pH reached 1. The temperature was controlled so that the temperature did not exceed 10 °C. The reaction mixture was extracted with ethyl acetate (100 mL × 3), the layers were separated, and the organic phases were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and rotary evaporated to give the crude intermediate A-1-2-1-9b (7.5 g, 22.22 mmol, yield 83.40%). MS-ESI: [M+H] + =237.1

[0201] In step 2, A-1-2-1-9b (7.5 g, 22.22 mmol) and resorcinol (2.45 g, 22.22 mmol) were added to a dry 100 mL three-neck flask, dissolved in methanesulfonic acid (30 mL), and the mixture was heated to 50 °C and reacted for 4 hours (preferably 4 to 8 hours). When LCMS showed the reaction was complete, the reaction mixture was slowly added to ethanol (100 mL) to control the quench temperature. The reaction mixture was then added to water (100 mL), extracted with ethyl acetate (200 mL x 3), and the layers were separated. The combined organic phases were washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, and rotary evaporated to give the crude intermediate A-1-2-1-9c (2.5 g, 8.86 mmol, 33.88% yield). MS-ESI:[MH] - =281.1

[0202] In step 3, A-1-2-1-9c (1.62 g, 5.57 mmol), A-1-2-1-1d (2.0 g, 6.39 mmol), potassium carbonate (1.77 g, 12.78 mmol), and tetrabutylammonium iodide (2.36 g, 6.39 mmol) were added to a dry 100 mL three-neck flask in this order, dissolved in acetone (30 mL), and stirred at room temperature for 8 hours (preferably 8 to 12 hours) to react. LCMS showed that the reaction was complete, and the insoluble matter was filtered off, the solvent was removed by spin drying, water (30 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3), and the layers were separated. The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1) to give intermediate A-1-2-1-9d (2.00 g, 1.27 mmol, yield 60.86%). MS-ESI:[MH] - =513.2

[0203] In step 4, A-1-2-1-9d (2.00 g, 1.27 mmol) was dissolved in dichloromethane (10 mL) in a dry 100 mL three-neck flask, trifluoroacetic acid (10 mL) was added, and the mixture was stirred and reacted for 4 hours (preferably 4 to 8 hours). LCMS showed the reaction was complete, and the solvent was removed by spin drying. The product A-1-2-1-9 (905.2 mg, 0.92 mmol, 48.13% yield, 95.03% purity) was obtained by silica gel column chromatography (PE:EA = 2:1). MS-ESI:[MH] - =457.2 1 H NMR (400 MHz, chloroform-d) δ 8.80 (t, J = 1.8 Hz, 1H), 8.35 (dt, J = 7.8, 1.4 Hz, 1H), 8.29 (dt, J = 7.9, 1.5 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.42 (ddd, J = 8.3, 7.5, 1.8 Hz, 1H), 7.18 (dd, J = 7.5, 1.8 Hz, 1H), 7.10(d,J=8.8Hz,1H),7.05-6.96(m,2H),6.76(s,2H),6.21(s,1H),5.62(d,J=6.9 Hz,1H),3.99(dq,J=10.7,7.1Hz,2H),1.79(d,J=6.8Hz,3H),1.14(t,J=7.0Hz,3H).

[0204] [Production Example (3) 8: Compound A-2-2-1-4] [ka] In step 1, A-2-2-1-4a (2.00 g, 11.22 mmol) was placed in a dry 100 mL three-neck flask and the flask was flushed with nitrogen. Anhydrous tetrahydrofuran (20 mL) was then added and dissolved, the temperature was lowered to 0°C, and pyridinium bromide perbromide (4.31 g, 13.46 mmol) was added in several portions. After all of the contents were added, the temperature was raised to 25°C and the mixture was allowed to react for 6 hours (preferably 6 to 8 hours). When LCMS showed that the reaction was complete, the reaction solution was filtered, the filtrate was collected, the filtrate was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), and the layers were separated. The organic phases were combined, washed with saturated sodium bicarbonate solution (50 mL), saturated sodium chloride solution (50 mL), respectively, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 2:1) to obtain intermediate A-2-2-1-4b (1.10 g, 4.28 mmol, yield 38.12%). MS-ESI:[MH] - =255.0

[0205] In step 2, A-2-2-1-4b (1.1 g, 4.28 mmol), A1-1-1c (1.12 g, 3.85 mmol), potassium carbonate (1.18 g, 8.56 mmol), and tetrabutylammonium iodide (1.58 g, 4.28 mmol) were added to a dry 100 mL three-neck flask in this order and dissolved in acetone (10 mL). After stirring overnight at room temperature, LCMS showed the reaction was complete. The mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 2:1) to give intermediate A-2-2-1-4c (1.00 g, 2.14 mmol, 50.06% yield). MS-ESI:[MH] - =465.1

[0206] In step 3, A-2-2-1-4c (1.00 g, 2.14 mmol) was added to a dry 100 mL three-neck flask, dissolved in 4 mL of tetrahydrofuran, cooled to 0 °C, and 2 M sodium hydroxide solution (2 mL) was added dropwise. The mixture was stirred and reacted for 1 hour (preferably 1-2 hours). LCMS showed the reaction was complete, and the mixture was diluted with water (10 mL). 2 M hydrochloric acid solution was added at 0 °C to quench the reaction and adjust the pH to 1. The mixture was extracted with ethyl acetate (5 mL × 3), separated, and the combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (DCM:MeOH = 15:1) to obtain the final product A-2-2-1-4 (117.4 mg, 0.08 mmol, yield 10.29%, purity 85.01%). MS-ESI:[MH] - =451.1 1 H NMR(400MHz,DMSO-d6)δ 8.52(t,J=1.8Hz,1H),8.25(ddt,J=10.7,7.8,1.4Hz,2H),7.76-7.64(m,2H),7.57(dd,J=8.6,6.1Hz, 1H),7.44(td,J=8.5,2.6Hz,1H),7.25(d,J=2.3Hz,1H),6.99-6.93(m,2H),6.32(s,1H),5.83(s,2H).

[0207] [Production Example (3) 9: Compound A-1-2-1-33] [ka] In step 1, A-1-2-1-33a (20.00 g, 68.81 mmol) and ethyl (2S)-2-hydroxypropionate (9.75 g, 82.57 mmol) were added to a dry 500 mL three-neck flask, dissolved in tetrahydrofuran (300 mL), and added with triphenylphosphine (21.66 g, 82.57 mmol) and diisopropyl azodicarboxylate (16.70 g, 82.57 mmol) in an ice bath. After stirring in an ice bath for 2 hours, the reaction was monitored by TLC and was complete. The reaction was quenched by adding water (200 mL), extracted with ethyl acetate (200 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA = 10:1) to obtain intermediate A-1-2-1-33b (30.00 g, crude product). MS-ESI: [M+H]+=391.1

[0208] In step 2, A-1-2-1-33b (30.00 g, crude product) was placed in a 500 mL single-neck flask, dissolved in tetrahydrofuran (150 mL) and methanol (50 mL), added with aqueous sodium hydroxide (2N, 100 mL), and stirred in an ice bath for 20 minutes. After sampling and spotting, TLC showed the starting material had completely reacted. The reaction was then stopped. Water (100 mL) was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate (100 mL x 3). The aqueous phase was quenched by dropwise addition of dilute hydrochloric acid (1N, 200 mL) to the aqueous phase, adjusted to a weak acidic state, and extracted with ethyl acetate (100 mL x 3). The combined organic phases were sampled for LCMS analysis and purified by silica gel column chromatography (DCM:MeOH = 15:1) to yield intermediate A-1-2-1-33c (14.40 g, crude product). MS-ESI:[MH] - =361.1

[0209] In step 3, A-1-2-1-33c (450 mg, 1.24 mmol) and ((3-(2-methoxy-2-oxyethyl)phenyl)boronic acid (530 mg, 2.48 mmol) were added to a dry 50 mL three-neck flask, and the flask was purged with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (72 mg, 0.062 mmol) was then added and dissolved in 5 mL of dioxane. Finally, dimethyl dicarbonate (330 mg, 2.48 mmol) was added. The reaction was carried out at 115°C for 2 hours (preferably 2-4 hours), and the reaction was monitored. When LCMS showed that the reaction was complete, the reaction was cooled to room temperature and filtered. The filtrate was collected, added with 10 mL of water, extracted with ethyl acetate (10 mL x 3), washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 3:1) to obtain intermediate A-1-2-1-33d (400 mg, 0.81 mmol, yield 65.15%). MS-ESI: [M+H] + =495.1

[0210] In step 4, A-1-2-1-33d (400 mg, 0.81 mmol) was added to a dry 50 mL three-neck flask and dissolved in 2 mL of tetrahydrofuran. The mixture was cooled to 0 °C, and 2 mL of 2 M aqueous sodium hydroxide was added. The mixture was then reacted for 30 minutes (preferably 0.5 to 2 hours). When TLC showed the reaction was complete, the pH was adjusted to 1 with 1 M aqueous hydrochloric acid, extracted with ethyl acetate (5 mL x 3), washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, spin-dried, and purified via silica gel column chromatography (DCM:MeOH = 10:1) to obtain the desired product A-1-2-1-33 (86 mg, 0.178 mmol, 22.0% yield). MS-ESI:[MH] - =479.1 1H NMR (400 MHz, chloroform-d) δ 8.01-7.94(m,2H),7.60-7.55(m,1H),7.49(td,J=7.7,1.7Hz,1H),7.30-7. 27(m,1H),7.26-7.23(m,1H),7.12(tdd,J=8.3,4.1,2.5Hz,1H),6.94(dd,J= 8.8,4.9Hz,1H),6.83-6.78(m,1H),6.77-6.71(m,1H),6.17(d,J=0.9Hz,1H ),5.61(qd,J=6.9,3.4Hz,1H),3.74(d,J=1.9Hz,2H),1.75(d,J=6.8Hz,3H).

[0211] [Production Example (3) 10: Compound A-1-10-1-21] [ka] In step 1, A-1-2-1-33c (450 mg, 1.24 mmol) and A-1-10-1-21a (460 mg, 2.48 mmol) were placed in a dry 50 mL three-neck flask, and after purging with nitrogen, tetrakis(triphenylphosphine)palladium(0) (72 mg, 0.062 mmol) was added and dissolved in 2 mL of dioxane solution. Finally, dimethyl dicarbonate (0.33 g, 2.48 mmol) was added and the mixture was stirred at 115°C for 2 hours (preferably The reaction was monitored for 2-4 hours, and when LCMS showed the reaction was complete, it was cooled to room temperature and filtered. The collected filtrate was added with 10 mL of water, extracted with ethyl acetate (10 mL x 3), washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 3:1) to obtain intermediate A-1-10-1-21b (210 mg, 0.43 mmol, yield 34.77%). MS-ESI:[MH] - =485.4

[0212] In step 2, A-1-10-1-21b (210 mg, 0.43 mmol) was added to a dry 50 mL three-neck flask and dissolved in 2 mL of tetrahydrofuran. The mixture was cooled to 0 °C, and 2 mL of 2 M aqueous sodium hydroxide was added. The mixture was then reacted for 30 minutes (preferably 0.5 to 2 hours). When TLC showed the reaction was complete, the pH was adjusted to 1 with 1 M aqueous hydrochloric acid, extracted with ethyl acetate (5 mL x 3), washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, spin-dried, and purified via silica gel column chromatography (DCM:MeOH = 10:1) to obtain the desired product A-1-10-1-21 (52 mg, 0.109 mmol, 25.3% yield). MS-ESI:[MH] - =471.0 1 H NMR(400MHz,chloroform-d)δ 7.93(d,J=4.1Hz,1H),7.83(d,J=4.0Hz,1H),7.29(dd,J=8.4,2.5Hz,1H),7.25(d,J=5.9Hz,1H),7.13(tt,J=8.3,2.4Hz, 1H),6.98(dd,J=8.4,2.5Hz,1H),6.92-6.73(m,2H),6.21(d,J=0.8Hz,1H),5.25(q,J=6.8Hz,1H),1.79(d,J=6.9Hz,3H).

[0213] [Production Example (3) 11: Compound A-1-10-1-19] [ka] In step 1, A-1-2-1-33c (500 mg, 1.38 mmol) and A-1-10-1-19a (469 mg, 2.76 mmol) were placed in a dry 50 mL three-neck flask, and after purging with nitrogen, tetrakis(triphenylphosphine)palladium(0) (80 mg, 0.069 mmol) was added and dissolved in 5 mL of dioxane solution. Finally, dimethyl dicarbonate (463 mg, 3.45 mmol) was added and the mixture was stirred at 115°C for 2 hours (preferably The reaction was monitored for 2-4 hours, and when LCMS showed the reaction was complete, it was cooled to room temperature and filtered. The filtrate was collected, added with 10 mL of water, extracted with ethyl acetate (10 mL x 3), washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 3:1) to obtain intermediate A-1-10-1-19b (317 mg, 0.67 mmol, yield 65.15%). MS-ESI: [M+H] + =471.1

[0214] In step 2, A-1-10-1-19b (317 mg, 0.67 mmol) was added to a dry 50 mL three-neck flask and dissolved in 2 mL of tetrahydrofuran. The mixture was cooled to 0 °C, and 2 mL of 2 M aqueous sodium hydroxide was added. The mixture was then reacted for 30 minutes (preferably 0.5 to 2 hours). When TLC showed the reaction was complete, the pH was adjusted to 1 with 1 M aqueous hydrochloric acid, extracted with ethyl acetate (5 mL x 3), washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain the desired product A-1-10-1-19 (104.8 mg, 0.23 mmol, 31.67% yield). MS-ESI:[MH] - =455.0 1H NMR(400MHz,DMSO-d6)δ 7.76-7.65(m,2H),7.54(dd,J=8.6,6.1Hz,1H),7.41(tt,J=8.5,3.2Hz,1H),6.99(dd,J=6.6,2.4Hz,1H),6 .98-6.91(m,2H),6.87(ddd,J=8.7,5.7,2.5Hz,1H),6.31(s,1H),5.91-5.77(m,1H),1.59(d,J=6.4Hz,3H).

[0215] [Production Example (3) 12: Compound A-1-2-1-44] [ka] In step 1, A-1-2-1-33c (1.00 g, 2.76 mmol) and A-1-2-1-44a (1.18 g, 5.52 mmol) were added to a dry 100 mL three-neck flask and purged with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.16 g, 0.14 mmol) was then added and dissolved in 15 mL of dioxane. Finally, dimethyl dicarbonate (0.74 g, 5.52 mmol) was added and the mixture was reacted at 115 °C for 2 hours. Then, (5-(methoxycarbonyl)furan-2-yl)boronic acid (469 mg, 2.76 mmol) was added and purged with nitrogen. Then, tetrakis(triphenylphosphine)palladium(0) (0.16 g, 0.14 mmol) was added and dissolved in 15 mL of dioxane. Add methyl (0) (80 mg, 0.069 mmol) and dissolve in 5 mL of dioxane solution. Finally, add dimethyl dicarbonate (463 mg, 3.45 mmol) and react at 115 °C for 2 hours (preferably 2 to 4 hours). Monitor the reaction. When LCMS shows the reaction is complete, cool to room temperature, filter, collect the filtrate, add 10 mL of water, extract with ethyl acetate (10 mL × 3), wash with 20 mL of saturated brine, dry with anhydrous sodium sulfate, and purify by silica gel column chromatography (PE:EA = 3:1) to obtain intermediate A-1-2-1-44b (0.33 g, 0.64 mmol, yield 23.13%). MS-ESI:[MH] - =513.1

[0216] In step 2, A-1-2-1-44b (300 mg, 0.58 mmol) was added to a dry 50 mL three-neck flask and dissolved in 2 mL of tetrahydrofuran. The mixture was cooled to 0 °C, and 2 mL of 2 M aqueous sodium hydroxide was added. The mixture was then reacted for 30 minutes (preferably 0.5 to 2 hours). When TLC showed the reaction was complete, the pH was adjusted to 1 with 1 M aqueous hydrochloric acid, extracted with ethyl acetate (5 mL x 3), washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain the desired product A-1-2-1-44 (15 mg, 0.03 mmol, 4.66% yield). LCMS: [MH] - =498.9 1 H NMR(400MHz,chloroform-d)δ 8.69(s,1H),8.13(d,J=8.4Hz,1H),7.61(d,J=8.4Hz,1H),7.30-7.27(m,1H),7.24(s,1H),7.16-7.05(m,1H) ),6.95(dd,J=8.8,3.0Hz,1H),6.87-6.64(m,2H),6.18(s,1H),5.51(d,J=6.9Hz,1H),1.78(d,J=6.8Hz,3H).

[0217] [Production Example (3) 13: Compound A-1-2-1-60] [ka] In step 1, A-1-2-1-60a (20.00 g, 76.65 mmol), tert-butyl 2-bromoacetate (1.36 g, 6.99 mmol), and potassium carbonate (1.61 g, 11.65 mmol) were added to a dry 500 mL three-neck flask, dissolved in 12 mL of acetone, and stirred at 25 °C for 6 hours (preferably 6 to 10 hours). When LCMS showed the reaction was complete, 10 mL of water was added, extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1) to give intermediate A-1-2-1-60b (1.20 g, 4.54 mmol, 97.40% yield). MS-ESI:[M- t Bu] + =209.2

[0218] In step 2, in a dry 100 mL three-neck flask, A-1-2-1-60b (1.20 g, 4.54 mmol) and pyridinium bromide perbromide (1.45 g, 4.54 mmol) were dissolved in 12 mL of tetrahydrofuran and stirred at 25 °C for 2 hours (preferably 2 to 4 hours). LCMS showed the reaction was complete. After filtration to remove insoluble salts, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1) to give intermediate A-1-2-1-60c (1.20 g, 3.83 mmol, 77.01% yield). 1 H NMR (400 MHz, chloroform-d) δ 7.62 (dt, J = 7.7, 1.4 Hz, 1H), 7.52 (dq, J = 2.7, 1.5 Hz, 1H), 7.39 (tt, J = 7.9, 1.7 Hz, 1H), 7.15 (ddt, J = 8.4, 2.8, 1.3 Hz, 1H), 5.27 (q, J = 6.6 Hz, 1H), 4.57 (q, J = 1.7 Hz, 2H), 1.88 (dt, J = 6.7, 1.6 Hz, 3H), 1.49 (t, J = 1.5 Hz, 9H).

[0219] In step 3, A-1-2-1-60c (1.20 g, 3.83 mmol) was added to a dry 100 mL three-neck flask and dissolved in 10 mL of acetone. Tetrabutylammonium iodide (1.41 g, 3.83 mmol) and potassium carbonate (1.06 g, 7.66 mmol) were added and stirred to disperse the mixture. Dichloromethane was then added, and finally A-1-1-1c (0.85 g, 5.75 mmol) was added and stirred at room temperature overnight. When LCMS showed that the reaction was complete, the reaction solution was filtered, the filtrate was collected, diluted with 10 mL of water, extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (DCM:MeOH = 15:1, 1:1000). AcOH) to give intermediate A-1-2-1-60d (0.86 g, 1.56 mmol, 44.48% yield). MS-ESI:[MH] - =551.2

[0220] In step 4, A-1-2-1-60d (860 mg, 1.56 mmol) was dissolved in trifluoroacetic acid (10 mL) and 10 mL of dichloromethane in a dry 50 mL three-neck flask and reacted at 25 °C for 2 hours (preferably 2 to 4 hours). When TLC showed the reaction was complete, water (20 mL) was added to quench the reaction. The reaction solution was extracted with ethyl acetate (20 mL x 3), washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 2:1) to obtain the desired product A-1-2-1-60a (386 mg, 0.78 mmol, 49.53% yield). MS-ESI:[MH] - =495.1 1H NMR(400MHz,chloroform-d)δ 7.68(d,J=7.6Hz,1H),7.56(dd,J=5.3,2.6Hz,1H),7.44(t,J=8.0Hz,1H),7.30-7.26(m,1H),7.25-7.19(m,2H),7.12(ddd,J=11.5,7.8,3.2H z,1H),6.94(dd,J=9.2,3.6Hz,1H),6.83-6.67(m,2H),6.17(s,1H),5.58(q,J=6.8Hz,1H),4.74(d,J=1.4Hz,2H),1.74(dd,J=6.7,1.4Hz,3H).

[0221] [Production Example (3) 14: Compound A-1-2-1-93] [ka] In step 1, compound A-1-2-1-93a (4.10 g, 18.72 mmol) and methoxy(methyl)amine hydrochloride (1.39 g, 20.59 mmol) were dissolved in N,N-dimethylformamide (40 mL) in a dry 100 mL three-neck flask. Benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (7.81 g, 20.59 mmol), 1-hydroxybenzotriazole (2.78 g, 20.59 mmol), and N,N-diisopropylethylamine (12.1 g, 93.6 mmol) were added in an ice bath and the reaction was allowed to proceed at room temperature for 2 hours. The reaction was quenched by adding water and extracted three times with ethyl acetate. The organic phases were combined, washed with 1 M hydrochloric acid, 1 M sodium hydroxide, and saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product. The crude product was purified by silica gel column chromatography (0-10% EA:PE) to obtain a colorless oily substance, A-1-2-1-93b (4.85 g, 17.58 mmol, yield 93.91%, purity 95%). MS-ESI: [M+H] + =261.9

[0222] In step 2, compound A-1-2-1-93b (4.35 g, 16.6 mmol) was dissolved in anhydrous tetrahydrofuran (87 mL) in a dry 100 mL three-neck flask, and ethylmagnesium bromide (2 M, 12.45 mL, 24.9 mmol) was added dropwise in an ice bath. After the addition was complete, the mixture was allowed to react at room temperature for 1 hour. The reaction was quenched by the addition of saturated ammonium chloride and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and spun to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 20:1) to obtain a white solid A-1-2-1-93c (3.87 g, 15.91 mmol, 95.86% yield, 95% purity). 1 H NMR (600 MHz, chloroform-d) δ 7.88 (t, J = 1.6 Hz, 1H), 7.58 (ddd, J = 8.9, 2.4, 1.4 Hz, 1H), 7.44 (ddd, J = 7.7, 2.5, 1.7 Hz, 1H), 2.96 (q, J = 7.2 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H).

[0223] In step 3, compound A-1-2-1-93c (3.90 g, 16.88 mmol) was dissolved in anhydrous N,N-dimethylformamide (87 mL) in a dry 100 mL three-neck flask, and cuprous cyanide (4.54 g, 50.64 mmol) was added. The mixture was purged with nitrogen four times and then refluxed at 185 °C under nitrogen protection for 3 hours (a large amount of bubbles began to form from the reaction, which disappeared upon complete reaction). The mixture was concentrated under reduced pressure to remove the N,N-dimethylformamide, and then 50 mL of water and 120 mL of ethyl acetate were added. The mixture was stirred for 10 minutes, filtered, and the cake was washed with ethyl acetate. The filtrate was allowed to settle and separated, and the aqueous phase was extracted once with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product, which was purified by silica gel column chromatography (PE:EA=20:1) to obtain a white solid A-1-2-1-93d (2.08 g, 11.62 mmol, yield 68.86%, purity 99%). 1H NMR (400 MHz, chloroform-d) δ 8.04 (t, J = 1.4 Hz, 1H), 7.89 (ddd, J = 8.8, 2.5, 1.4 Hz, 1H), 7.55 (ddd, J = 7.5, 2.6, 1.4 Hz, 1H), 3.00 (q, J = 7.2 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H).

[0224] In step 4, compound A-1-2-1-93d (2.08 g, 11.74 mmol) was dissolved in dioxane (17.60 mL) in a dry 100 mL three-neck flask, and aqueous sodium hydroxide solution (4 M, 17.6 mL, 70.44 mmol) was added. The mixture was then incubated at 95 °C for 3 hours. The mixture was cooled to room temperature, diluted with water, and washed once with ethyl acetate. The aqueous phase was adjusted to pH 2-3 with concentrated hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain a colored solid, A-1-2-1-93e (2.03 g, 9.83 mmol, 83.74% yield, 95% purity). MS-ESI:[MH] - =195.3

[0225] In step 5, compound A-1-2-1-93e (1.93 g, 9.84 mmol) was dissolved in tert-butanol (19 mL) in a dry 100 mL three-neck flask, and 4-dimethylaminopyridine (481 mg, 3.94 mmol) and di-tert-butyl dicarbonate (2.58 g, 25.58 mmol) were added. The reaction was allowed to proceed at room temperature for 3 hours. TLC confirmed the reaction was complete. The reaction solution was spin-dried, dissolved in ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium bicarbonate solution, and saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain a white solid A-1-2-1-93f (1.25 g, 4.71 mmol, 47.84% yield, 95% purity). 1H NMR (400 MHz, chloroform-d) δ 8.34 (t, J = 1.4 Hz, 1H), 7.83 (dddd, J = 11.9, 8.9, 2.6, 1.4 Hz, 2H), 3.03 (q, J = 7.2 Hz, 2H), 1.62 (s, 9H), 1.24 (t, J = 7.2 Hz, 3H).

[0226] In step 6, in a dry 50 mL three-neck flask, compound A-1-2-1-93f (100 mg, 396.38 μmol) was dissolved in dichloromethane (1 mL), 48% hydrobromic acid (4.5 μL) was added, and bromine (63 mg, 396.38 μmol, 20.4 μL) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 16 hours. One equivalent of bromine (63 mg, 396.38 μmol, 20.4 μL) was added, and the reaction continued at room temperature for 3 hours. Upon completion of the reaction as detected by LCMS, the reaction solution was dried over anhydrous sodium sulfate and spun down to obtain the crude product compound A-1-2-1-93g (107 mg, 350.09 μmol, 88.32% yield, 90% purity) as a pale yellow solid. MS-ESI:[MH] - =273.2

[0227] In step 7, in a dry 50 mL three-neck flask, compound A1-1-1-1c (101 mg, 368.11 μmol) was dissolved in anhydrous acetonitrile (1 mL), triethylamine (112 mg, 1.10 mmol), and compound A-1-2-1-93g (107 mg, 368.11 μmol) were added. The reaction was allowed to proceed at room temperature for 5 hours, and the reaction was confirmed by LCMS. The mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product, which was purified by medium-pressure reverse-phase chromatography to obtain a white solid, A-1-2-1-93 (43 mg, 85.15 μmol, 23.13% yield, 95.34% purity). MS-ESI: [M+H] + =485.4 1H NMR(400MHz,DMSO-d6)δ 13.65(s,1H),8.37(q,J=1.3Hz,1H),8.19(dq,J=9.1,2.2Hz,1H),7.99(ddd,J=8.7,2.6,1.4Hz,1H),7.69(dt,J=8.9,2.3Hz,1H),7.56(ddd,J=8 .6,6.1,2.6Hz,1H),7.43(tdd,J=8.5,4.1,2.5Hz,1H),7.13(dd,J=3.5,2.3Hz,1H),6.98-6.86(m,2H),6.35-6.25(m,2H),1.58(d,J=6.7Hz,3H).

[0228] [Production Example (3) 15: Compound A-1-2-1-40] [ka] In step 1, compound A-1-2-1-40a (2.00 g, 9.94 mmol), methoxymethylamine (1.05 g, 10.44 mmol), triethylamine (1.06 g, 10.44 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.00 g, 10.44 mmol) were dissolved in N,N-dimethylformamide (30 mL) in a dry 100 mL three-neck flask and reacted at room temperature for 3 hours. The mixture was concentrated to remove the N,N-dimethylformamide, and water was added. The mixture was extracted three times with ethyl acetate. The organic phases were combined and spun dry. The crude product was purified by silica gel column chromatography to give a colorless liquid A-1-2-1-40b (1.77 g, 6.17 mmol, 62.10% yield, 85% purity). MS-ESI: [M+H] + =244.9

[0229] In step 2, compound A-1-2-1-40b (1.77 g, 7.26 mmol) was dissolved in tetrahydrofuran (35 mL) in a dry 10 mL three-neck flask, and ethylmagnesium bromide (14.5 mL, 29.05 mmol) was added dropwise at 0 °C. The reaction was allowed to proceed at room temperature for 2 hours. The reaction was quenched at 0 °C by the addition of saturated ammonium chloride solution and extracted three times with ethyl acetate. The organic phases were combined and spun dry. The crude product was purified by silica gel column chromatography to give a colorless liquid A-1-2-1-40c (718 mg, 3.37 mmol, 46.36% yield, 95% purity). MS-ESI: [M+H] + =214.2

[0230] In step 3, compound A-1-2-1-40d (718 mg, 3.37 mmol) and hydrobromic acid (272 mg, 3.37 mmol) were dissolved in dichloromethane (15 mL) in a dry 50 mL three-neck flask, and bromine (538 mg, 3.37 mmol) was added at 0 °C. The mixture was allowed to react at room temperature for 3 hours. The solvent was removed by concentration. The crude product was purified by silica gel column chromatography to give a colorless liquid A-1-2-1-40e (700 mg, 2.40 mmol, 71.16% yield, 100% purity). MS-ESI: [M+H] + =292.2

[0231] In step 4, A1-1-1c (200 mg, 688 μmol), compound A-1-2-1-40e (201 mg, 688 μmol), and dicesium carbonate (560 mg, 1.72 mmol) were dissolved in acetonitrile (10 mL) in a dry 50 mL three-neck flask and reacted at room temperature for 2 hours. The reaction mixture was filtered and then purified by high-pressure reverse-phase preparative chromatography and silica gel normal-phase chromatography to give a colored solid, A-1-2-1-40 (45 mg, 88 μmol, yield 12.86%, purity 98.7%). 1H NMR(400MHz,DMSO-d6)δ 8.42(t,J=1.8Hz,1H),8.35(ddd,J=7.0,2.9,1.3Hz,1H),8.13(dt,J=8.1, 1.2Hz,1H),7.81(t,J=7.8Hz,1H),7.69(dt,J=8.9,2.4Hz,1H),7.59-7.50 (m,3H),7.42(tdd,J=8.5,4.1,2.6Hz,1H),7.09(dd,J=5.2,2.4Hz,1H),6. 98-6.86(m,2H),6.35-6.30(m,1H),6.29-6.22(m,1H),1.68-1.53(m,3H). ESI-LCMS: m / z [M+H] + 502.0

[0232] [Production Example (3) 16: Compound A-1-2-1-94] [ka] In step 1, compound A-1-2-1-94a (500 mg, 2.69 mmol) and 4-dimethylaminopyridine (83 mg, 671 μmol) were dissolved in dichloromethane (20 mL) in a dry 50 mL three-neck flask, and acetyl chloride (232 mg, 2.95 mmol) was added dropwise at room temperature. The mixture was allowed to react at 25 °C for 1.5 hours. The mixture was concentrated to remove the dichloromethane. The crude product was purified by silica gel column chromatography to give a white solid, A-1-2-1-94b (248 mg, 1.09 mmol, 40.46% yield, 98% purity). MS-ESI: [M+H] + =229.0

[0233] In step 2, compound A-1-2-1-94b (248 mg, 1.09 mmol) and hydrobromic acid (88 mg, 1.09 mmol) were dissolved in dichloromethane (8 mL) in a dry 50 mL three-neck flask. Bromine (521 mg, 3.26 mmol) was added at 0 °C and the mixture was allowed to react at 20 °C for 16 hours. The mixture was concentrated to remove the dichloromethane. The crude product was purified by silica gel column chromatography to give a yellow solid A-1-2-1-94c (281 mg, 915 μmol, 84.20% yield, 95% purity). MS-ESI: [M+H] + =307.0

[0234] In step 3, compound A-1-2-1-94c (295 mg, 960 μmol), A1-1-1c (279 mg, 960 μmol), and dicesium carbonate (782 mg, 2.40 mmol) were dissolved in acetonitrile (8 mL) in a dry 50 mL three-neck flask and reacted at 40 °C for 3 hours. The reaction mixture was filtered and then purified by high-pressure reverse-phase preparative chromatography to give a white solid, A-1-2-1-94 (52 mg, 104 μmol, yield 10.84%, purity 95.1%). MS-ESI: [M+H] + =474.9 1 H NMR(600MHz,DMSO-d6)δ 11.59(s,1H),7.82(dt,J=7.4,1.4Hz,2H),7.69(dt,J=8.8,2.8Hz,1H),7.55(ddd,J=8.5,6.1,2.4Hz,1H),7.46-7.40(m,1H),7.02(dd,J=8.0 ,2.5Hz,1H),6.94(d,J=8.9Hz,1H),6.86(ddd,J=13.1,8.9,2.5Hz,1H),6.31(d,J=1.3Hz,1H),6.21-6.14(m,1H),1.55(dd,J=6.7,1.6Hz,3H).

[0235] [Production Example (3) 17: Compound A-1-11-1-1] [ka] In step 1, in a dry 100 mL three-neck flask, compound A-1-11-1-1a (4.00 g, 24.82 mmol) and N-methoxy(methyl)amine hydrochloride (2.88 g, 29.78 mmol) were dissolved in N,N-dimethylformamide (30 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (12.26 g, 32.27 mmol) and N,N-diisopropylethylamine (9.62 g, 74.46 mmol) were added in that order. The mixture was stirred at room temperature for 2 hours, followed by addition of water and extraction with ethyl acetate. The organic phases were combined, dried, filtered, and spun to dryness to obtain the crude product, which was then purified using reverse phase chromatography to obtain a white solid A-1-11-1-1b (3.30 g, 16.16 mmol, 65.10% yield). MS-ESI: [M+H] + =205.0

[0236] In step 2, in a dry 100 mL three-neck flask, A-1-11-1-1b (2.00 g, 9.79 mmol) was dissolved in tetrahydrofuran (20 mL), and ethylmagnesium bromide (2 M, 24.48 mL) was slowly added to the reaction solution in an ice bath. The temperature was raised to 50 °C and the reaction was continued for 10 hours. The reaction solution was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phases were combined, dried, filtered, and purified using normal phase chromatography to give A-1-11-1-1c (840 mg, 4.12 mmol, 42.09% yield) as a yellow oil. MS-ESI: [M+H] + =174.2

[0237] In step 3, A-1-11-1-1c (860 mg, 4.97 mmol) was dissolved in tetrahydrofuran (10 mL) in a dry 50 mL three-neck flask, sodium hydride (179 mg, 7.45 mmol) was added, and the mixture was stirred in an ice bath for 30 minutes. p-Toluenesulfonyl chloride (644 mg, 7.45 mmol) was added, and the mixture was allowed to react at room temperature for 2 hours. The mixture was quenched with water and extracted with ethyl acetate. The combined organic phases were dried, filtered, and spun to dryness to give the crude product, which was purified using normal phase chromatography to give A-1-11-1-1d (1.00 g, 3.05 mmol, 61.52% yield) as a yellow solid. MS-ESI: [M+H] + =328.0

[0238] In step 4, in a dry 50 mL three-neck flask, compound A-1-11-1-1d (290 mg, 885.78 μmol) was dissolved in tetrahydrofuran (3 mL), and trimethylphenylammonium tribromide (399 mg, 1.06 mmol) was added. The mixture was reacted at room temperature for 2 hours, filtered, and spun dry to give A-1-11-1-1e (359 mg, crude product), which was used directly in the next step. MS-ESI: [M+H] + =405.9

[0239] In step 5, in a dry 50 mL three-neck flask, compounds A-1-11-1-1e (634 mg, crude product) and A1-1-1c (381 mg, 1.30 mmol) were dissolved in acetonitrile (10 mL), potassium carbonate (180 mg, 1.30 mmol) was added, and the mixture was reacted at 45 °C for 2 hours. The mixture was filtered and the solvent was removed by spin drying to obtain the crude product, which was then purified using normal phase chromatography to obtain a gray solid A-1-11-1-1f (530 mg, 857.51 μmol, 65.87% yield). MS-ESI: [M+H] + =616.4

[0240] In step 6, in a dry 50 mL three-neck flask, compound A-1-11-1-1f (250 mg, 404.48 μmol) was dissolved in methanol (10 mL) and tetrahydrofuran (5 mL), and dicesium carbonate (263 mg, 808.97 μmol) was added. The mixture was reacted at 55 °C for 2 hours, filtered, and the solvent was removed by spin drying. The mixture was then purified using reverse phase chromatography to give a white solid A-1-11-1-1 (70 mg, 150.90 μmol, 37.31% yield). MS-ESI: [M+H] + =462.4 1 H NMR(600MHz,DMSO-d6)δ 11.59(br.s,1H),8.51(t,J=2.1Hz,1H),7.80(dd,J=8.5,1.7Hz,1H),7.68(ddd,J=8.9,4.4,2.6Hz,1H),7.57-7.49( m,3H),7.41(qd,J=8.3,2.6Hz,1H),7.01-6.85(m,3H),6.65(s,1H),6.34-6.22(m,2H),1.61(dd,J=6.7,1.7Hz,3H).

[0241] [Production Example (3) 18: Compound A-1-10-1-4] [ka] In step 1, compound A-1-10-1-4a (1.20 g, 9.9 mmol) was dissolved in chloroform (15 mL) and ethyl acetate (15 mL) in a dry 50 mL three-neck flask, and copper dibromide (4.40 g, 19.9 mmol) was added at room temperature. The temperature was raised to 65 °C and the reaction was carried out for 5 hours. The crude product was filtered and the solvent was removed by spin drying to obtain the crude product, which was then purified using reverse phase chromatography to obtain a gray solid A-1-10-1-4b (500 mg, 2.47 mmol, 24.78% yield). MS-ESI: [M+H] + =202.0

[0242] In step 2, in a dry 50 mL three-neck flask, compounds A-1-10-1-4b (100 mg, 494.92 μmol) and A1-1-1c (110 mg, 380.7 μmol) were dissolved in acetonitrile (5 mL), potassium carbonate (131 mg, 0.95 mmol) was added, and the mixture was reacted at 45 °C for 10 hours. The crude product was filtered and spun dry to obtain the product, which was then purified using reverse phase chromatography to obtain a pink solid A-1-10-1-4 (66 mg, 160.27 μmol, 42.1% yield, 95% purity). 1 H NMR(400MHz,DMSO-d6)δ 12.00(s,1H),7.68(dt,J=8.9,2.4Hz,1H),7.54(ddd,J=8.7,6.1,1.3Hz,1H),7.41(tdd,J=8.5,3.6,2.5Hz,1H),7.33(ddt,J=4.8,3.5,2.0Hz,1H ),7.26-7.11(m,1H),7.01-6.91(m,2H),6.88(ddd,J=8.9,3.7,2.4Hz,1H ),6.37-6.23(m,2H),5.76(p,J=6.5Hz,1H),1.58(dd,J=6.6,1.3Hz,3H). MS-ESI: [M+H] + =412.0

[0243] [Production Example (3) 19: Compound A-1-10-1-5] [ka] In step 1, in a dry 50 mL three-neck flask, compound A-1-10-1-5a (1.00 g, 9.00 mmol) and N-methoxymethylamine (1.13 g, 11.70 mmol, hydrochloride salt) were dissolved in N,N-dimethylformamide (15 mL) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.42 g, 11.7 The reaction mixture was added in this order, and the temperature was slowly raised to 60°C overnight. The reaction was quenched by adding water, extracted with ethyl acetate, and the combined organic phases were dried, filtered, and spun to dryness to give the crude product, which was then purified using reverse phase chromatography to give a white solid, A-1-10-1-5b (1.20 g, 4.67 mmol, 51.89% yield, 60% purity). MS-ESI: [M+H] + =155.1

[0244] In step 2, compound A-1-10-1-5b (1.10 g, 4.28 mmol) was dissolved in dichloromethane (20 mL) in a dry 50 mL three-neck flask, and di-tert-butyl dicarbonate (1.39 g, 6.42 mmol), triethylamine (650 mg, 6.42 mmol), and 4-dimethylaminopyridine (52 mg, 428.11 μmol) were added in that order. The reaction was allowed to proceed at room temperature for 2 hours, and the solvent was removed by spin drying. Normal-phase purification afforded A-1-10-1-5c (410 mg, 1.61 mmol, 37.66% yield) as a white oil. MS-ESI: [M+H] + =255.0

[0245] In step 3, in a dry 50 mL three-neck flask, compound A-1-10-1-5c (410 mg, 1.61 mmol) was dissolved in tetrahydrofuran (5 mL), and ethylmagnesium bromide (2 M, 2.42 mL) was added in an ice bath. After the entire mixture was added, the mixture was allowed to warm to room temperature and react for 2 hours. The reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, and the organic phases were combined, dried, filtered, spin-dried, and purified using normal phase chromatography to obtain A-1-10-1-5d (270 mg, 1.21 mmol, 75.00% yield) as a colorless oil. MS-ESI: [M+H] + =224.4

[0246] In step 4, in a dry 50 mL three-neck flask, compound A-1-10-1-5d (352 mg, 1.58 mmol) was dissolved in chloroform (5 mL) and ethyl acetate (5 mL), copper dibromide (703 mg, 3.15 mmol) was added, and the mixture was heated to 65 °C for 2 h, LCMS showed that the product was mainly the product, which was filtered and spun dry to give A-1-10-1-5e (318 mg, crude), which was used directly in the next step. MS-ESI: [M+H] + =201.9

[0247] In step 5, compounds A-1-10-1-5e (318 mg, 1.57 mmol) and A1-1-1c (458 mg, 1.57 mmol) were dissolved in acetonitrile (10 mL) in a dry 50 mL three-neck flask, potassium carbonate (434 mg, 3.15 mmol) was added, and the mixture was reacted at 45 °C for 10 hours. The crude product was filtered and spin-dried, and then purified by reverse phase chromatography and high performance liquid chromatography to give A-1-10-1-5c (60 mg, 144.97 μmol, yield 9.23%, purity 99.5%). MS-ESI: [M+H] + =412.0 1H NMR(400MHz,DMSO-d6)δ 11.67(s,1H),7.86(tt,J=3.4,1.6Hz,1H),7.68(dt,J=8.9,2.3Hz,1H),7.54(ddd,J=8.6,6.1,1.2Hz,1H),7.41(tdd,J=8.5,3. 7,2.5Hz,1H),7.00-6.78(m,4H),6.56(q,J=2.3Hz,1H),6.29(d,J=1.4Hz,1H),5.77-5.63(m,1H),1.55(dd,J=6.6,1.1Hz,3H).

[0248] [Production Example (3) 20: Compound A-2-2-1-1] [ka] In step 1, tetrahydrofuran (10 mL) and pentamethylenebis(magnesium bromide) (1.23 g, 4.4 mmol) were added to a dry 50 mL three-neck flask, and copper(I) cyanide di(lithium chloride) complex solution (589 mg, 4.4 mL, 4.4 mmol) was added dropwise to the three-neck flask at -78 °C. The mixture was allowed to react for 30 minutes, after which A-2-2-1-1a (1.00 g, 4.37 mmol) was added at -78 °C. Once the mixture was added, the mixture was allowed to react at room temperature for 1 hour. After this, isobutyric acid chloride (698 mg, 6.55 mmol) was added and the mixture was allowed to react for 30 minutes, after which sampling was performed to monitor the reaction. After the reaction was completed, the reaction was quenched with saturated ammonium chloride, extracted with EA three times, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product, which was purified on a silica gel column (petroleum ether:ethyl acetate=10:1) to obtain A-2-2-1-1b (560 mg, 2.91 mmol, yield 66.64%). MS-ESI: [M+H] + =174.3

[0249] In step 2, A-2-2-1-1b (560 mg, 2.91 mmol) was dissolved in methanol (10 mL) in a dry 50 mL three-neck flask, concentrated sulfuric acid (2.1 mL) was added, and the temperature was raised to 70 °C for 2 hours, followed by sampling and monitoring. After the reaction was completed, the pH was adjusted to neutral by adding 1N sodium hydroxide solution, poured into water, extracted three times with dichloromethane, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain crude product A-2-2-1-1c (471 mg, crude product). MS-ESI: [M+H] + =207.3

[0250] In step 3, A-2-2-1-1c (400 mg, crude product) was placed in a dry 50 mL three-neck flask and dissolved in tetrahydrofuran (5 mL). Lithium hydroxide (93 mg, 0.29 mmol), methanol (4 mL), and water (2 mL) were added and the reaction was continued for 2 hours, followed by sampling and monitoring. After the reaction was complete, the pH was adjusted with HCl, the mixture was poured into water, extracted three times with dichloromethane, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to give the crude product A-2-2-1-1d (364 mg, crude product). MS-ESI: [M+H] + =193.3

[0251] In step 4, compound A-2-2-1-1d (364 mg, crude product) was added to a dry 50 mL three-neck flask and dissolved in dichloromethane (5 mL). Di-tert-butyl dicarbonate (455 mg, 2.08 mmol) and 4-dimethylaminopyridine (231 mg, 1.89 mmol) were added and the reaction was allowed to proceed for 2 hours. After the reaction was complete, the mixture was poured into water, extracted three times with dichloromethane, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to give crude product A-2-2-1-1e (520 mg, crude product). MS-ESI: [M+H] + =249.1

[0252] In step 5, A-2-2-1-1e (520 mg, crude product) was placed in a dry 50 mL three-neck flask and dissolved in dichloromethane (5 mL). Hydrobromic acid (35 mg, 0.20 mmol) and bromine (397 mg, 2.51 mmol) were added at 0 °C. The reaction was allowed to proceed at room temperature for 2 hours, after which sampling was performed to monitor the reaction. After the reaction was complete, the mixture was concentrated and spin-dried to give the crude product A-2-2-1-1f (635 mg, crude product). MS-ESI: [M+H] + =327.3

[0253] In step 6, compound A-2-2-1-1f (600 mg, crude product) was added to a dry 50 mL three-neck flask and dissolved in N,N-dimethylformamide (10 mL). Further addition of A1-1-1c (596 mg, 2.02 mmol) and dicesium carbonate (1.49 g, 4.58 mmol) was performed for 16 hours, after which sampling was performed. After completion of the reaction, the mixture was poured into water, extracted three times with EA, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was purified by passing through a silica gel column (DCM:MeOH = 10:1) to obtain A-2-2-1-1g (110 mg, 0.20 mmol, 11.14% yield). MS-ESI: [M+H] + =495.1

[0254] In step 7, compound A-2-2-1-1g (80 mg, 0.15 mmol) was added to a dry 50 mL three-neck flask, dissolved in dichloromethane (2.5 mL), and then TFA (2.5 mL) was added. The reaction was allowed to proceed at room temperature for 2 hours, after which sampling was performed. After the reaction was complete, the mixture was concentrated and spin-dried to obtain the crude product, which was purified by MPLC to obtain compound A-2-2-1-1 (52 mg, 0.10 mmol, 66.6% yield). MS-ESI: [M+H] + =481.2 1H NMR(400MHz,DMSO-d6)δ 13.29(s,1H),8.71(t,J=1.8Hz,1H),8.36(d,J=7.9Hz,1H),8.12(dt,J=7.8,1.4Hz,1H),7.74-7. 56(m,2H),7.58-7.34(m,2H),6.89(d,J=8.8Hz,1H),6.82-6.66(m,2H),6.30(s,1H),1.76(s,6H).

[0255] [Production Example (3) 21: Compound A-1-2-1-83] [ka] In step 1, A-1-2-1-83a (1.50 g, 9.99 mmol), N,N-dimethylformamide (20 mL), imidazole (2.04 g, 30 mmol), and tert-butyldimethylchlorosilane (3.01 g, 19.98 mmol) were added to a 200 mL single-neck flask in this order. After all ingredients were added, the mixture was stirred at room temperature for 6 hours. After TLC showed complete reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash chromatography to give compound A-1-2-1-83b (2.00 g, 7.56 mmol, 76% yield). MS-ESI: [M+H] + =265.2

[0256] In step 2, compound A-1-2-1-83b (500 mg, 1.89 mmol), tetrahydrofuran (10 mL), pyrrolidone hydrobromide (1.23 g, 3.78 mmol), and 2-pyrrolidone (322 mg, 3.78 mmol) were added to a 100 mL single-neck flask in this order. Once all the ingredients were added, the reaction was allowed to proceed at 60 °C for 6 hours. TLC monitoring indicated complete reaction. The reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash chromatography to give compound A-1-2-1-83c (400 mg, 1.17 mmol, 62% yield). MS-ESI: [M+H] + =343.1

[0257] In step 3, compound A-1-2-1-83c (380 mg, 1.11 mmol), intermediate A1-1-1c (355 mg, 1.22 mmol), tetrabutylammonium iodide (820 mg, 2.22 mmol), potassium carbonate (307 mg, 2.22 mmol), and N,N-dimethylformamide (10 mL) were added to a 100 mL single-neck flask in this order. After all the ingredients were added, the mixture was allowed to react at room temperature overnight. LCMS showed the reaction was complete. The reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash chromatography to give compound A-1-2-1-83d (110 mg, 0.25 mmol, 23% yield). MS-ESI: [M+H] + =439.1 1H NMR(400MHz,DMSO-d6)δ 10.76(d,J=1.7Hz,1H),7.97(dd,J=8.8,1.3Hz,2H),7.68(dt,J=8.9,2.6Hz,1H),7.54(dd,J=8.6,6.1Hz,1H),7.41(tdd,J=8.5,4.4, 2.5Hz,1H),6.98-6.89(m,4H),6.84(ddd,J=9.1,7.0,2.5Hz,1H),6.29(d,J=1.1Hz,1H),6.12(p,J=6.7Hz,1H),1.54(d,J=6.7Hz,3H).

[0258] In step 4, intermediate A-1-2-1-83d (40 mg, 0.09 mmol) and N,N-diisopropylethylamine (24 mg, 0.18 mmol) were dissolved in dichloromethane (2 mL) in a 50 mL single-neck flask. Acetyl chloride (11 mg, 0.14 mmol) was slowly added dropwise to the solution at room temperature. Once the starting materials were added, the reaction was allowed to proceed at room temperature for 2 hours. Upon completion of the reaction, monitored by LCMS, the reaction mixture was diluted with dichloromethane (50 mL) and washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by prep-TLC to give compound A-1-2-1-83 (20 mg, 0.04 mmol, 44% yield). MS-ESI: [M+H] + =481.1 1 H NMR(400MHz,chloroform-d)δ 8.10(d,J=8.8Hz,2H),7.35-7.26(m,2H),7.26-7.21(m,2H),7.12(tt,J=8.2,2.8Hz,1H),6.94(dd,J=8. 8,3.9Hz,1H),6.85-6.68(m,2H),6.17(s,1H),5.55(q,J=6.8Hz,1H),2.34(s,3H),1.76(d,J=6.8Hz,3H).

[0259] [Production Example (3) 22: Compound A-1-2-1-89] [ka] In step 1, A-1-2-1-89a (360 mg, 2 mmol), tetrahydrofuran (10 mL), pyrrolidone hydrobromide (1.30 g, 4 mmol), and 2-pyrrolidone (340 mg, 4 mmol) were added to a 100 mL single-neck flask in this order. Once all the ingredients were added, the reaction was allowed to proceed at 60 °C for 6 hours. After TLC monitoring showed the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash chromatography to give compound A-1-2-1-89b (400 mg, 1.55 mmol, 77% yield). MS-ESI:[MH] - =256.0

[0260] In step 2, compound A-1-2-1-89b (380 mg, 1.47 mmol), A1-1-1c (470 mg, 1.62 mmol), tetrabutylammonium iodide (1.09 g, 2.94 mmol), potassium carbonate (406 mg, 2.94 mmol), and N,N-dimethylformamide (10 mL) were added to a 100 mL single-neck flask in this order. Once all the materials were added, the reaction was allowed to proceed overnight at room temperature. LCMS monitoring indicated complete reaction. The reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash chromatography to give compound A-1-2-1-89 (140 mg, 0.30 mmol, 20% yield). MS-ESI: [M+H] + =468.1 1H NMR(400MHz,chloroform-d)δ 8.91(q,J=1.9Hz,1H),8.47(ddd,J=8.2,2.3,1.0Hz,1H),8.38(dd,J=7.8,1.4Hz,1H),7.72(t,J=8.0Hz,1H),7.32-7.23(m,2H),7.13(tt ,J=7.8,2.3Hz,1H),6.97(dd,J=8.8,2.6Hz,1H),6.85-6.74(m,2H),6.19(d,J=1.0Hz,1H),5.55(q,J=6.9Hz,1H),1.81(d,J=6.8Hz,3H).

[0261] [Production Example (3) 23: Compound A-1-10-1-39] [ka] In step 1, A-1-10-1-39a (150 mg, 1.05 mmol), tetrahydrofuran (5 mL), pyrrolidone hydrobromide (684 mg, 2.10 mmol), and 2-pyrrolidone (179 mg, 2.10 mmol) were added to a 50 mL single-neck flask in this order. Once all the ingredients were added, the reaction was allowed to proceed at 60 °C for 6 hours. After TLC monitoring showed the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash chromatography to give compound A-1-10-1-39b (400 mg, 1.55 mmol, 77% yield). 1 H NMR(400MHz,chloroform-d)δ 4.55(q,J=6.7Hz,1H),4.02(dtd,J=11.5,4.5,2.3Hz,2H),3.46(td,J=11.0,2.4 Hz,2H),3.09(tt,J=11.4,3.9Hz,1H),1.96-1.62(m,4H),1.75(d,J=6.8Hz,3H).

[0262] In step 2, A-1-10-1-39b (190.0 mg, 0.86 mmol), intermediate A1-1-1c (225.0 mg, 0.77 mmol), tetrabutylammonium iodide (635.0 mg, 1.72 mmol), potassium carbonate (238.0 mg, 1.72 mmol), and N,N-dimethylformamide (5 mL) were added to a 50 mL single-neck flask in this order. Once all the starting materials were added, the reaction was allowed to proceed overnight at room temperature. LCMS monitoring indicated complete reaction. The reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by prep-TLC to give compound A-1-10-1-39 (110.0 mg, 0.26 mmol, 30% yield). MS-ESI: [M+H] + =431.1 1 H NMR(400MHz,chloroform-d)δ 7.33(dd,J=8.5,2.7Hz,2H),7.17(td,J=8.3,2.6Hz,1H),7.01(d,J=8.7Hz,1H),6.86-6.73(m,2H),6.24(s,1H),4.86(q,J=6. 8Hz,1H),4.07-3.94(m,2H),3.45(ddt,J=25.8,13.8,7.5Hz,2H),3.09-2.98(m,1H),1.89-1.68(m,4H),1.59(d,J=6.8Hz,3H).

[0263] [Production Example (3) 24: Compound A-1-1-1-15] [ka] In step 1, A-1-1-1-15a (450.0 mg, 3.16 mmol), tetrahydrofuran (5 mL), pyrrolidone hydrobromide (1.03 g, 3.16 mmol), and 2-pyrrolidone (269.0 mg, 3.16 mmol) were added to a 50 mL single-neck flask in this order. Once all the ingredients were added, the reaction was allowed to proceed at room temperature for 4 hours. After TLC showed the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give the crude product A-1-1-1-15b (500.0 mg), which was used directly in the next step.

[0264] In step 2, intermediate A-1-1-1-15a (500.0 mg, 2.26 mmol, crude), intermediate A-1-1-1c (657.0 mg, 2.26 mmol), tetrabutylammonium iodide (1.25 g, 3.39 mmol), potassium carbonate (625.0 mg, 4.52 mmol), and N,N-dimethylformamide (10 mL) were added to a 100 mL single-neck flask in this order. After all the starting materials were added, the reaction mixture was allowed to react at room temperature for 3 hours. LCMS monitoring indicated complete reaction. The reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash chromatography to give compound A-1-1-1-15 (110.0 mg, 0.26 mmol, 11% yield). MS-ESI:[MH] - =429.2 1H NMR(400MHz,chloroform-d)δ 7.32(dt,J=8.7,2.7Hz,2H),7.17(td,J=8.2,2.4Hz,1H),7.00(d,J=8.7Hz,1H),6.86-6.69(m,2H),6.22(s,1H),4.74(q,J=6.8Hz ,1H),2.65(dt,J=18.5,7.4Hz,1H),2.45(dt,J=17.9,7.3Hz,1H),1.57(t,J=6.1Hz,5H),1.31-1.19(m,6H),0.88(t,J=6.6Hz,3H).

[0265] [Production Example (3) 25: Compound A-1-2-1-73] [ka] In step 1, compound A-1-2-1-73a (213.0 mg, 1 mmol), tetrahydrofuran (5 mL), pyrrolidone hydrobromide (652.0 mg, 2 mmol), and 2-pyrrolidone (170.0 mg, 2 mmol) were added to a 100 mL single-neck flask in this order. After all the ingredients were added, the reaction was allowed to proceed at 60 °C for 2 hours. TLC monitoring revealed complete reaction. The reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash chromatography to give compound A-1-2-1-73b (250.0 mg, 0.86 mmol, 86% yield). MS-ESI: [M+H] + =292.9

[0266] In step 2, compound A-1-2-1-73b (250.0 mg, 0.86 mmol), intermediate A1-1-1c (165.0 mg, 0.57 mmol), tetrabutylammonium iodide (211.0 mg, 0.57 mmol), potassium carbonate (158.0 mg, 1.14 mmol), and N,N-dimethylformamide (10 mL) were added to a 100 mL single-neck flask in this order. After all the ingredients were added, the reaction was allowed to proceed at room temperature for 3 hours. LCMS monitoring indicated complete reaction. The reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash chromatography to give compound A-1-2-1-73 (226.0 mg, 0.45 mmol, 52% yield). MS-ESI: [M+H] + =501.0 1 H NMR(400MHz,DMSO-d6)δ 8.23(d,J=1.9Hz,1H),8.08(dd,J=8.0,1.5Hz,1H),7.93(dd,J=7.8,2.0Hz,1H),7.70(dt,J=8.9,2.4Hz,1H),7.60-7.53(m,2H),7.48-7.37(m ,1H),7.09(dd,J=5.0,2.4Hz,1H),6.95(d,J=8.9Hz,1H),6.89(td,J=8.5,2.4Hz,1H),6.32(s,1H),6.30-6.21(m,1H),1.56(d,J=6.7Hz,3H).

[0267] [Production Example (3) 26: Compound A-1-2-1-90] [ka] In step 1, compound A-1-2-1-90a (100.0 mg, 0.63 mmol), tetrahydrofuran (5 mL), pyrrolidone hydrobromide (411.0 mg, 1.26 mmol), and 2-pyrrolidone (107.0 mg, 1.26 mmol) were added to a 100 mL single-neck flask in this order. After all the ingredients were added, the reaction was allowed to proceed at 60 °C for 2 hours. TLC monitoring revealed complete reaction. The reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash chromatography to give compound A-1-2-1-9b (118.0 mg, 0.50 mmol, 79% yield). MS-ESI: [M+H] + =237.9

[0268] In step 2, compound A-1-2-1-90b (118.0 mg, 0.50 mmol), intermediate A1-1-1c (145.0 mg, 0.50 mmol), tetrabutylammonium iodide (185.0 mg, 0.50 mmol), potassium carbonate (138.0 mg, 1 mmol), and N,N-dimethylformamide (2.5 mL) were added to a 100 mL single-neck flask in this order. After all the ingredients were added, the reaction was allowed to proceed at room temperature for 3 hours. LCMS monitoring indicated complete reaction. The reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash chromatography to give compound A-1-2-1-90 (30.5 mg, 0.07 mmol, 14% yield). MS-ESI: [M+H] + =448.1 1H NMR(400MHz,DMSO-d6)δ 8.58(q,J=1.6Hz,1H),8.31(dt,J=8.0,1.5Hz,1H),8.18(dt,J=7.7,1.4Hz,1H),7.80( t,J=7.8Hz,1H),7.69(dt,J=8.9,2.3Hz,1H),7.56(ddd,J=8.5,6.1,2.4Hz,1H),7.42( tdd,J=8.5,4.1,2.6Hz,1H),7.11(dd,J=3.9,2.3Hz,1H),6.94(d,J=8.7Hz,1H),6.92- 6.87(m,1H),6.32(d,J=0.9Hz,1H),6.29(td,J=6.8,4.0Hz,1H),1.57(d,J=6.8Hz,3H).

[0269] [Production Example (3) 27: Compound A-1-10-1-3] [ka] In step 1, A-1-10-1-3a (200.0 mg, 1.47 mmol), tetrahydrofuran (5 mL), pyrrolidone hydrobromide (951.0 mg, 2.92 mmol), and 2-pyrrolidone (248.0 mg, 2.92 mmol) were added to a 50 mL single-neck flask in this order. Once all the ingredients were added, the reaction was allowed to proceed at 60 °C for 6 hours. After TLC monitoring showed the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash chromatography to give compound A-1-10-1-3b (182.0 mg, 0.85 mmol, 58% yield). MS-ESI: [M+H] + =215.0

[0270] In step 2, compound A-1-10-1-3b (182.0 mg, 0.85 mmol), intermediate A1-1-1c (163.0 mg, 0.56 mmol), tetrabutylammonium iodide (310.0 mg, 0.84 mmol), potassium carbonate (232.0 mg, 1.68 mmol), and N,N-dimethylformamide (5 mL) were added to a 50 mL single-neck flask in this order. After all the ingredients were added, the mixture was allowed to react overnight at room temperature. LCMS showed the reaction was complete. The reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash chromatography to give compound A-1-10-1-3 (39.0 mg, 0.09 mmol, 16% yield). MS-ESI: [M+H] + =425.1 1 H NMR(400MHz,DMSO-d6)δ 9.17(s,1H),9.00(d,J=2.4Hz,1H),8.89(s,1H),7.69(dt,J=8.9,2.5Hz,1H),7.55(ddd,J=8.7,6.2,2.7Hz,1H),7.46-7 .38(m,1H),7.00(dd,J=6.8,2.2Hz,1H),6.88(ddd,J=12.3,11.0,5.5Hz,2H),6.34-6.27(m,2H),1.65(d,J=6.8Hz,3H).

[0271] [Production Example (3) 28: Compound A-1-10-1-6] [ka] In step 1, A-1-10-1-6a (2.00 g, 17.84 mmol), dichloromethane (50 mL), dimethylhydroxylamine hydrochloride (3.50 g, 35.88 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.10 g, 26.60 mmol), and 1-hydroxybenzotriazole (3.60 g, 26.64 mmol) were added to a 100 mL single-neck flask in this order. After all the ingredients were added, the reaction was allowed to proceed at 25 °C for 16 hours. After TLC and LCMS showed complete reaction, the reaction mixture was diluted with dichloromethane (100 mL), washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. It was then filtered and rotary evaporated. The crude product was purified by flash chromatography to give compound A-1-10-1-6b (1.80 g, 11.60 mmol, 65% yield). MS-ESI: [M+H] + =156.1

[0272] In step 2, compound A-1-10-1-6c (1.80 g, 11.60 mmol) and tetrahydrofuran (20 mL) were added to a 100 mL single-neck flask, and the mixture was protected by nitrogen purging. The temperature was then cooled to -15 °C, and a solution of ethylmagnesium bromide in tetrahydrofuran (2 M, 11.6 mL, 23.2 mmol) was slowly added dropwise. After the reaction mixture was added, the mixture was allowed to warm to room temperature and react for 4 hours. LCMS and TLC monitoring showed the reaction was complete. The mixture was quenched by the addition of saturated aqueous ammonium chloride (100 mL), extracted with ethyl acetate (100 mL x 3), and the combined organic layer was washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash chromatography to give compound A-1-10-1-6c (1.10 g, 8.86 mmol, 76% yield). MS-ESI: [M+H] + =125.1

[0273] In step 3, compound A-1-10-1-6c (400.0 mg, 3.22 mmol), tetrahydrofuran (10 mL), pyrrolidone hydrobromide (2.10 g, 6.44 mmol), and 2-pyrrolidone (548.0 mg, 6.44 mmol) were added to a 100 mL single-neck flask. After all the starting materials were added, the mixture was allowed to warm to room temperature and react for 6 hours. After monitoring by LCMS and TLC, the reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash chromatography to give compound A-1-10-1-6d (210.0 mg, 1.03 mmol, 32% yield). MS-ESI: [M+H] + =203.0

[0274] In step 4, compound A-1-10-1-6d (210.0 mg, 1.03 mmol), intermediate A1-1-1c (198.0 mg, 0.68 mmol), tetrabutylammonium iodide (380.0 mg, 1.03 mmol), potassium carbonate (285.0 mg, 2.06 mmol), and N,N-dimethylformamide (10 mL) were added to a 50 mL single-neck flask in this order. After all the ingredients were added, the mixture was allowed to react overnight at room temperature. After completion of the reaction, monitored by LCMS and TLC, the reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash chromatography to give compound A-1-10-1-6 (43.0 mg, 0.10 mmol, 15% yield). MS-ESI: [M+H] + =413.1 1H NMR(400MHz,DMSO-d6)δ 9.17(s,1H),9.00(d,J=2.4Hz,1H),8.89(s,1H),7.69(dt,J=8.9,2.5Hz,1H),7.55(ddd,J=8.7,6.2,2.7Hz,1H),7.46-7 .38(m,1H),7.00(dd,J=6.8,2.2Hz,1H),6.88(ddd,J=12.3,11.0,5.5Hz,2H),6.34-6.27(m,2H),1.65(d,J=6.8Hz,3H).

[0275] [Production Example (3) 29: Compound A-1-2-1-78] [ka] In step 1, A-1-2-1-78a (1.00 g, 6.70 mmol) and tetrahydrofuran (20 mL) were added to a 100 mL three-neck flask and stirred thoroughly. After thorough stirring, di-tert-butyl dicarbonate (1.61 g, 7.38 mmol) and 4-dimethylaminopyridine (0.08 g, 0.67 mmol) were added in that order and the mixture was allowed to react overnight at room temperature. The reaction was monitored by LCMS and TLC. Upon completion, the mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed first with saturated aqueous sodium bicarbonate and then with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound A-1-2-1-78b (0.56 g, 2.25 mmol, 34% yield). MS-ESI: [M+H] + =250.1

[0276] In step 2, A-1-2-1-78b (0.40 g, 1.60 mmol) and tetrahydrofuran (20 mL) were added to a 100 mL three-neck flask and thoroughly dissolved. Then, pyrrolidone (0.16 g, 1.92 mmol) and pyrrolidone hydrobromide (0.78 g, 2.40 mmol) were added to the reaction system, in that order, and the reaction temperature was raised to 50 °C for 6 hours. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to give compound A-1-2-1-78c (0.32 g, 0.97 mmol, 61% yield). MS-ESI: [M+H] + =328.1

[0277] In step 3, compound A-1-2-1-78c (0.20 g, 0.61 mmol) and A1-1-1c (0.16 g, 0.55 mmol) were added to a 50 mL three-neck flask, and then acetone (10 mL) was added to dissolve the mixture thoroughly. Potassium carbonate (0.17 g, 1.22 mmol) and tetrabutylammonium iodide (0.23 g, 0.61 mmol) were added in that order, and the reaction was allowed to proceed at room temperature for 3 hours. After completion of the reaction, the mixture was monitored by TLC and LCMS. The mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give compound A-1-2-1-78d (0.16 g, 0.30 mmol, 49% yield). MS-ESI: [M+H] + =538.1

[0278] In step 4, compound A-1-2-1-78d (0.10 g, 0.19 mmol) and dichloromethane (3 mL) were added to a 50 mL three-neck flask and stirred thoroughly. Trifluoroacetic acid (3 mL) was added dropwise to the solution and the reaction was allowed to proceed at room temperature for 10 minutes. The reaction was monitored by TLC and LCMS. Upon completion of the reaction, the reaction was quenched with saturated sodium bicarbonate solution (20 mL), diluted with water, and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give compound A-1-2-1-78 (0.05 g, 0.11 mmol, 58% yield). MS-ESI: [M+H] + =438.2 1 H NMR(400MHz,DMSO-d6)δ 7.81(d,J=8.6Hz,2H),7.73-7.64(m,1H),7.55(dd,J=8.5,6.2Hz,1H),7.43(m,J=4.3Hz,1H),6.92(d,J=8.9Hz,1H),6.89 (dd,J=5.3,2.4Hz,1H),6.86-6.80(m,1H),6.61(d,J=8.7Hz,2H),6.30(s,3H),6.06-5.93(m,1H),1.54(d,J=6.6Hz,3H).

[0279] [Production Example (3) 30: Compound A-1-2-1-72] [ka] Compounds A-1-2-1-72a (0.50 g, 2.02 mmol) and A1-1-1c (0.53 g, 1.82 mmol) were added to a 50 mL three-neck flask, and then acetone (10 mL) was added to dissolve the mixture thoroughly. Potassium carbonate (0.56 g, 4.04 mmol) and tetrabutylammonium iodide (0.75 g, 2.02 mmol) were added in that order, and the mixture was allowed to react at room temperature for 3 hours. The reaction was monitored by TLC and LCMS. Upon completion, the mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give compound A-1-2-1-72 (0.16 g, 0.35 mmol, 20% yield). MS-ESI: [M+H] + =457.1 1 H NMR(400MHz,DMSO-d6)δ 8.10(s,1H),8.03(d,J=7.7Hz,1H),7.79(d,J=7.9Hz,1H),7.69(dd,J=8.9,2.1Hz,1H),7.63(t,J=7.9Hz,1H),7.55(t,J=7.3Hz,1H),7.46-7 .37(m,1H),7.08(dd,J=4.5,2.3Hz,1H),6.93(t,J=7.9Hz,1H),6.88(t,1H),6.31(s,1H),6.27(dd,J=9.2,4.2Hz,1H),1.55(d,J=6.7Hz,3H).

[0280] [Production Example (3) 31: Compound A-1-2-1-84] [ka] Compound A-1-2-1-84a (0.10 g, 0.23 mmol) and tetrahydrofuran (3 mL) were added to a 50 mL three-neck flask and thoroughly dissolved. Then, acetic anhydride (0.03 g, 0.28 mmol) was added dropwise to the reaction solution and allowed to react at room temperature overnight. The reaction was monitored by TLC and LCMS. Upon completion of the reaction, ethyl acetate (30 mL) was added to the reaction solution, washed with aqueous hydrochloric acid (1.0 M), and the aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed first with saturated aqueous sodium bicarbonate and then with saturated brine, and concentrated under reduced pressure. The crude product was purified by flash chromatography to obtain compound A-1-2-1-84 (0.06 g, 0.13 mmol, yield 57%). MS-ESI: [M+H] + =480.2 1 H NMR(400MHz,DMSO-d6)δ 10.37(s,1H),8.06(d,J=8.4Hz,2H),7.77(d,J=8.7Hz,2H),7.69(d,J=8.9Hz,1H),7.59-7.51(m,1H),7.47-7.35(m,1H),6.98(dd,J =5.9,2.1Hz,1H),6.93(d,J=8.9Hz,1H),6.89-6.81(m,1H),6.31(s,1H),6.16(t,J=6.7Hz,1H),2.10(s,3H),1.57(d,J=6.5Hz,3H).

[0281] [Production Example (3) 32: Compound A-1-2-1-79] [ka] Compound A-1-2-1-79a (0.50 g, 1.14 mmol) and acetone (10 mL) were added to a 50 mL three-neck flask and thoroughly dissolved. To the reaction mixture, iodomethane (1.62 g, 11.40 mmol) and sodium carbonate (0.36 g, 3.42 mmol) were added and the mixture was allowed to react at room temperature for 24 hours. The reaction was monitored by TLC and LCMS. Upon completion, the mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give compound P06 (0.13 g, 0.29 mmol, 25% yield). MS-ESI: [M+H] + =452.3 1 H NMR(400MHz,DMSO-d6)δ 7.87(d,J=8.5Hz,2H),7.69(dt,J=8.8,2.6Hz,1H),7.54(dd,J=8.5,6.2Hz,1H),7.46-7.37(m,1H),6.92(d,J=8.9Hz,1H),6.88(dd, J=5.2,2.4Hz,1H),6.86-6.80(m,1H),6.60(d,J=8.9Hz,2H),6.29(s,1H),6.02(t,J=6.9Hz,1H),2.76(s,3H),1.54(d,J=6.5Hz,3H).

[0282] [Production Example (3) 33: Compound A-1-2-1-80] [ka] Compound A-1-2-1-80a (0.50 g, 1.14 mmol) and acetone (10 mL) were added to a 50 mL three-neck flask and thoroughly dissolved. After that, iodomethane (1.62 g, 11.40 mmol) and sodium carbonate (0.36 g, 3.42 mmol) were added to the reaction solution and the mixture was allowed to react at room temperature for 24 hours. The reaction was monitored by TLC and LCMS. Upon completion, the mixture was diluted with water and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give compound A-1-2-1-80 (0.08 g, 0.17 mmol, 15% yield). MS-ESI: [M+H] + =466.2 1 H NMR(400MHz,DMSO-d6)δ 7.93(d,J=8.2Hz,2H),7.69(d,J=8.9Hz,1H),7.54(dd,J=8.5,6.2Hz,1H),7.46-7.35(m,1H),6.92(d,J=8.9Hz,1H),6.89(dd,J=5 .4,2.4Hz,1H),6.86-6.81(m,1H),6.77(d,J=9.0Hz,2H),6.29(s,1H),6.05(p,J=6.6Hz,1H),3.05(s,6H),1.54(d,J=6.5Hz,3H).

[0283] [Production Example (3) 34: Compound A-1-1-1-13] [ka] Compounds 3-bromo-2-butanone (0.20 g, 1.32 mmol) and A1-1-1c (0.35 g, 1.19 mmol) were added to a 50 mL three-neck flask, and then acetone (10 mL) was added to dissolve the mixture thoroughly. Potassium carbonate (0.36 g, 2.64 mmol) and tetrabutylammonium iodide (0.48 g, 1.32 mmol) were added in that order, and the reaction was allowed to proceed at room temperature for 3 hours. The reaction was monitored by TLC and LCMS. Upon completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give compound A-1-1-1-13 (0.26 g, 0.72 mmol, 62% yield). MS-ESI: [M+H] + =361.1 1 H NMR(400MHz,DMSO-d6)δ 7.75-7.69(m,1H),7.61-7.54(m,1H),7.48-7.41(m,1H),7.04(dd,J=6.5,2.4Hz,1H),6.95(d,J=8.9Hz ,1H),6.91-6.86(m,1H),6.33(s,1H),5.25-5.14(m,1H),2.23(d,J=1.2Hz,3H),1.49(d,J=6.8Hz,3H).

[0284] [Production Example (3) 35: Compound A-1-2-1-75] [ka] In step 1, A-1-2-1-75a (0.50 g, 3.37 mmol) and tetrahydrofuran (15 mL) were added to a 50 mL three-neck flask and thoroughly dissolved. Then, pyrrolidone (0.34 g, 4 mmol) and pyrrolidone hydrotribromide (1.65 g, 5.06 mmol) were added to the reaction system, in that order, and the reaction temperature was raised to 50 °C for 6 hours. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to give compound A-1-2-1-75b (0.71 g, 3.13 mmol, 93% yield).

[0285] In step 2, compound A-1-2-1-75b (0.15 g, 0.66 mmol) and A1-1-1c (0.17 g, 0.59 mmol) were added to a 50 mL three-neck flask, and then acetone (10 mL) was added to dissolve the mixture thoroughly. Potassium carbonate (0.18 g, 1.32 mmol) and tetrabutylammonium iodide (0.24 g, 0.66 mmol) were added in that order, and the reaction was allowed to proceed at room temperature for 3 hours. The reaction was monitored by TLC and LCMS. Upon completion, the mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give compound A-1-2-1-75 (0.12 g, 0.27 mmol, 47% yield). MS-ESI:[MH] - =435.1 1 H NMR(400MHz,DMSO-d6)δ 7.93(d,J=7.3Hz,2H),7.73(dt,J=8.9,2.6Hz,1H),7.61-7.55(m,2H),7.53(d,J=7.9Hz,1H),7.50-7.42(m,1H),7.04(dd,J=6.9,2 .4Hz,1H),6.98(d,J=8.9Hz,1H),6.94-6.87(m,1H),6.35(d,J=1.2Hz,1H),6.31-6.23(m,1H),2.44(s,3H),1.60(d,J=6.4Hz,3H).

[0286] [Production Example (3) 36: Compound A-1-2-1-76] [ka] In step 1, A-1-2-1-76a (0.20 g, 1.22 mmol) and tetrahydrofuran (10 mL) were added to a 50 mL three-neck flask and thoroughly dissolved. Then, pyrrolidone (0.12 g, 1.46 mmol) and pyrrolidone hydrobromide (0.59 g, 1.83 mmol) were added to the reaction system, in that order, and the reaction temperature was raised to 50 °C for 6 hours. After the reaction was completed as monitored by LCMS, the mixture was diluted with water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to give compound A-1-2-1-76b (0.22 g, 0.90 mmol, 74% yield).

[0287] In step 2, compound A-1-2-1-76b (0.20 g, 0.82 mmol) and A1-1-1c (0.22 g, 0.74 mmol) were added to a 50 mL three-neck flask, and then acetone (10 mL) was added to dissolve the mixture thoroughly. Potassium carbonate (0.23 g, 1.64 mmol) and tetrabutylammonium iodide (0.30 g, 0.82 mmol) were added in that order, and the reaction was allowed to proceed at room temperature for 3 hours. The reaction was monitored by TLC and LCMS. Upon completion, the mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give compound A-1-2-1-76 (0.16 g, 0.35 mmol, 46% yield). MS-ESI: [M+H] + =453.2 1H NMR(400MHz,DMSO-d6)δ 7.74-7.65(m,2H),7.59-7.47(m,3H),7.47-7.36(m,1H),7.30(dd,J=8.3,2.0Hz,1H),7.02(dd,J=6.8,2.2Hz,1H),6.94(d,J=8 .9Hz,1H),6.88(td,J=8.6,2.3Hz,1H),6.31(s,1H),6.27(dd,J=13.2,6.6Hz,1H),3.83(d,J=5.5Hz,3H),1.56(d,J=6.7Hz,3H).

[0288] [Production Example (3) 37: Compound A-1-2-1-70] [ka] In step 1, A-1-2-1-70a (0.30 g, 2.20 mmol) and dichloromethane (15 mL) were added to a 50 mL three-neck flask and dissolved thoroughly. Dess-Martin oxidant (1.40 g, 3.30 mmol) was then slowly added and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was monitored by TLC and LCMS. Upon completion, the mixture was diluted with ethyl acetate (30 mL). The reaction mixture was then filtered, washed once with water, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound A-1-2-1-70b (0.23 g, 1.71 mmol, 78% yield).

[0289] In step 2, A-1-2-1-70b (0.23 g, 1.71 mmol) and tetrahydrofuran (10 mL) were added to a 50 mL three-neck flask and thoroughly dissolved. Then, pyrrolidone (0.17 g, 2.05 mmol) and pyrrolidone hydrobromide (0.83 g, 2.56 mmol) were added to the reaction system, in that order, and the reaction temperature was raised to 50 °C for 6 hours. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to give compound A-1-2-1-70c (0.20 g, 0.94 mmol, 55% yield).

[0290] In step 3, compound A-1-2-1-70c (0.10 g, 0.47 mmol) and A1-1-1c (0.12 g, 0.42 mmol) were added to a 50 mL three-neck flask, and then acetone (10 mL) was added to dissolve the mixture thoroughly. Potassium carbonate (0.13 g, 0.94 mmol) and tetrabutylammonium iodide (0.17 g, 0.47 mmol) were added in that order, and the reaction was allowed to proceed at room temperature for 3 hours. The reaction was monitored by TLC and LCMS. Upon completion, the mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give compound A-1-2-1-70 (0.11 g, 0.26 mmol, 56% yield). MS-ESI:[MH] - =421.1 1 H NMR(400MHz,DMSO-d6)δ 8.09(d,J=7.8Hz,2H),7.71(dd,J=16.6,8.4Hz,2H),7.64-7.52(m,3H),7.43(dt,J=6.7,4.2Hz,1H),7.03(dd,J=6.0,1 .8Hz,1H),6.95(d,J=8.9Hz,1H),6.91-6.84(m,1H),6.31(s,1H),6.25(dd,J=13.0,6.5Hz,1H),1.58(d,J=6.6Hz,3H).

[0291] [Production Example (3) 38: Compound A-1-11-1-10] [ka] In step 1, A-1-11-1-10a (0.50 g, 2.81 mmol) and tetrahydrofuran (15 mL) were added to a 50 mL three-neck flask and thoroughly dissolved. Then, pyrrolidone (0.29 g, 3.37 mmol) and pyrrolidone hydrobromide (1.37 g, 4.22 mmol) were added to the reaction system in that order, and the reaction temperature was raised to 50 °C for 6 hours. After the reaction was completed as monitored by LCMS, the mixture was diluted with water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to give compound A-1-11-1-10b (0.42 g, 1.63 mmol, 58% yield).

[0292] In step 2, compounds A-1-11-1-10b (0.20 g, 0.78 mmol) and A-1-1c (0.20 g, 0.70 mmol) were added to a 50 mL three-neck flask, and then acetone (10 mL) was added to dissolve the mixture thoroughly. Potassium carbonate (0.22 g, 1.56 mmol) and tetrabutylammonium iodide (0.29 g, 0.78 mmol) were added in that order, and the reaction was allowed to proceed at room temperature for 3 hours. The reaction was monitored by TLC and LCMS. Upon completion, the mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give compound A-1-11-1-10 (0.18 g, 0.39 mmol, 50% yield). MS-ESI:[MH] - =465.1 1 H NMR(400MHz,DMSO-d6)δ 7.77(d,J=8.2Hz,1H),7.69(d,J=8.8Hz,1H),7.57(s,1H),7.54(d,J=6.6Hz,1H),7.43(dd,J=10.5,6.5Hz,1H),7.12(d,J= 8.2Hz,1H),7.00-6.94(m,1H),6.93(s,1H),6.86(t,J=8.1Hz,1H),6.31(s,1H),6.21-6.13(m,3H),1.55(d,J=6.6Hz,3H).

[0293] [Production Example (3) 39: Compound A-1-2-1-71] [ka] In step 1, A-1-2-1-71a (1.00 g, 6.57 mmol) and tetrahydrofuran (20 mL) were added to a 100 mL three-neck flask and thoroughly dissolved. Then, pyrrolidone (0.67 g, 7.88 mmol) and pyrrolidone hydrobromide (3.21 g, 9.86 mmol) were added to the reaction system in this order, and the reaction temperature was raised to 50 °C for 6 hours. After the reaction was completed as monitored by LCMS, the mixture was diluted with water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound A-1-2-1-71b (0.90 g, 3.90 mmol, 59% yield).

[0294] In step 2, compounds A-1-2-1-71b (0.20 g, 0.87 mmol) and A1-1-1c (0.23 g, 0.78 mmol) were added to a 50 mL three-neck flask, and then acetone (10 mL) was added to dissolve the mixture thoroughly. Potassium carbonate (0.24 g, 1.74 mmol) and tetrabutylammonium iodide (0.32 g, 0.87 mmol) were added in that order, and the reaction was allowed to proceed at room temperature for 3 hours. The reaction was monitored by TLC and LCMS. Upon completion, the mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give compound A-1-2-1-71 (0.12 g, 0.27 mmol, 31% yield). MS-ESI: [M+H] + =441.1 1H NMR(400MHz,DMSO-d6)δ 7.93(d,J=7.7Hz,1H),7.89(d,J=9.8Hz,1H),7.73-7.51(m,4H),7.47-7.38(m,1H),7.06(dd,J=4.8,2.3Hz,1H ),6.94(t,J=8.9Hz,1H),6.92-6.85(t,1H),6.31(s,1H),6.27(dt,J=11.9,6.0Hz,1H),1.56(d,J=6.6Hz,3H).

[0295] [Production Example (3) 40: Compound A-1-2-1-88] [ka] In step 1, A-1-2-1-88a (1.00 g, 4.95 mmol) and tetrahydrofuran (20 mL) were added to a 100 mL three-neck flask and thoroughly dissolved. Then, pyrrolidone (0.51 g, 5.94 mmol) and pyrrolidone hydrobromide (2.42 g, 7.43 mmol) were added to the reaction system in that order, and the reaction temperature was raised to 50 °C for 6 hours. After the reaction was completed as monitored by LCMS, the mixture was diluted with water and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound A-1-2-1-88b (0.90 g, 3.20 mmol, 65% yield).

[0296] In step 2, compound A-1-2-1-88b (0.30 g, 1.07 mmol) and A1-1-1c (0.28 g, 0.96 mmol) were added to a 50 mL three-neck flask, and then acetone (10 mL) was added to dissolve the mixture thoroughly. Potassium carbonate (0.30 g, 2.14 mmol) and tetrabutylammonium iodide (0.39 g, 1.07 mmol) were added in that order, and the mixture was heated to 60 °C. After completion of the reaction, the mixture was monitored by TLC and LCMS. The mixture was diluted with water and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give compound A-1-2-1-88 (0.40 g, 0.81 mmol, 76% yield). MS-ESI: [M+H] + =491.1 1 H NMR(400MHz,DMSO-d6)δ 7.91(dd,J=15.0,8.7Hz,2H),7.73-7.51(m,4H),7.47-7.38(m,1H),7.06(dd,J=4.8,2.3Hz,1H),6. 90(ddd,J=12.8,11.3,5.7Hz,2H),6.31(s,1H),6.27(dt,J=11.9,6.0Hz,1H),1.56(d,J=6.6Hz,3H).

[0297] [Production Example (3) 41: Compound A-1-7-1-1] [ka] A-1-7-1-1a (0.15 g, 0.32 mmol), formic acid (5 mL), and 37% formaldehyde (5 mL) were added to a 50 mL reaction flask, heated to 80 °C, and stirred. The reaction was monitored by TLC and LCMS. Upon completion of the reaction, the mixture was diluted with water and extracted with dichloromethane (50 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give compound A-1-7-1-1 (0.13 g, 0.29 mmol, 91% yield). MS-ESI: [M+H]+ =444.1 1 H NMR(400MHz,DMSO-d6)δ 7.72(d,J=8.8Hz,1H),7.57(dd,J=8.6,6.1Hz,1H),7.49-7.40(m,1H),7.03(dd,J=5.1,2.4Hz,1H),6.96(dd,J=8.8,1.4Hz,1H),6.91-6.83(m, 1H),6.34(s,1H),5.48-5.28(m,1H),2.99-2.71(m,3H),2.24(s,3H),1 .99(dd,J=38.5,26.3Hz,3H),1.73-1.51(m,3H),1.49(d,J=6.8Hz,3H).

[0298] [Production Example (3) 42: Compound A-1-7-1-4] [ka] A-1-7-1-4a (0.15 g, 0.32 mmol), 2-chloroethanol (0.14 g, 1.12 mmol), triethylamine (2 mL), and dioxane (10 mL) were added to a 50 mL three-neck flask and stirred at room temperature. The reaction was monitored by TLC and LCMS. Upon completion, the mixture was diluted with water and extracted with dichloromethane (50 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give compound A-1-7-1-4 (0.12 g, 0.25 mmol, 78.5% yield). MS-ESI: [M+H] + =474.1 1H NMR (400 MHz, DMSO-d6) δ 7.71(d,J=8.8Hz,1H),7.57(t,1H),7.44(t,J=8.4Hz,1H),7.00(dd,J=5.6,2.4 Hz,1H),6.95(dd,J=8.9,1.8Hz,1H),6.88-6.82(m,1H),6.32(s,1H),5.44-5.2 9(m,1H),4.35(t,J=5.4Hz,1H),3.46(dd,J=11.7,6.1Hz,2H),2.96-2.61(m,4H ),2.35(t,J=6.3Hz,2H),1.96(dt,J=20.8,11.6Hz,4H),1.46(d,J=10.8Hz,3H).

[0299] [Production Example (3) 43: Compound A-1-7-1-3] [ka] A-1-7-1-3a (0.15 g, 0.32 mmol), 2,2-dichloroacetic acid (0.10 g, 0.80 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.14 g, 0.38 mmol), triethylamine (1 mL), and dichloromethane (20 mL) were added to a dry 50 mL three-neck flask and stirred at room temperature. The reaction was monitored by TLC and LCMS. Upon completion, the mixture was diluted with water and extracted with dichloromethane (50 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give compound A-1-7-1-3 (0.13 g, 0.24 mmol, 74% yield). MS-ESI: [M+H] + =540.1 1H NMR (400 MHz, CD3OD) δ 7.50-7.42(m,2H),7.29(td,J=8.1,1.9Hz,1H),7.04(d,J=8.8Hz,1H),6.99 -6.95(m,1H),6.88(t,J=5.7Hz,2H),6.23(s,1H),5.20(td,J=6.8,4.1Hz,1 H),4.50-4.33(m,1H),4.09(dd,J=23.4,13.9Hz,1H),3.22(ddd,J=14.2,12 .4,3.0Hz,2H),3.01-2.77(m,1H),2.06(d,J=13.0Hz,1H),1.81-1.46(m,6H)

[0300] [Production Example (3) 44: Compound A-1-10-1-7] [ka] In step 1, A-1-10-1-7a (2.56 g, 19.96 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (9.11 g, 23.95 mmol), triethylamine (5.05 g, 49.90 mmol), and methoxyamine hydrochloride (2.14 g, 21.96 mmol) were dissolved in dichloromethane in a dry 50 mL three-neck flask. The mixture was added to ethanol (80 mL) and stirred at room temperature overnight. When TLC showed that the starting materials had completely reacted, the reaction mixture was washed first with 1.0 M hydrochloric acid (50 mL), then with 0.5% aqueous sodium carbonate (50 mL), and then with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give compound A-1-10-1-7b (3.24 g, 18.92 mmol, 95% yield).

[0301] In step 2, compound A-1-10-1-7b (3.24 g, 18.92 mmol) was added to a dry 50 mL three-neck flask, followed by the addition of tetrahydrofuran (40 mL). The temperature was cooled to -10 ° C., and 18 mL of ethyl magnesium bromide (2.0 M) was slowly added dropwise. The temperature was maintained for 30 minutes and slowly raised to room temperature. When TLC showed that the raw material was consumed, ethyl acetate (150 mL) and 5% ammonium chloride solution (50 mL) were added. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography to obtain compound A-1-10-1-7c (1.40 g, 9.99 mmol, 53% yield).

[0302] In step 3, in a dry 50 mL three-neck flask, A-1-10-1-7c (1.40 g, 9.99 mmol) and tribromopyridine (4.79 g, 14.99 mmol) were added to 20 mL of tetrahydrofuran, protected with nitrogen, and heated to 60 °C. When the raw materials were consumed as detected by TLC, ethyl acetate (150 mL) and 5% sodium dithionite solution (50 mL) were added, the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give compound A-1-10-1-7d (2.00 g, 9.13 mmol, yield 91%).

[0303] In step 4, compound A-1-10-1-7d (0.12 g, 0.55 mmol) and A1-1-1c (0.15 g, 0.50 mmol) were added to a dry 50 mL three-neck flask, followed by acetone (10 mL) to dissolve the mixture thoroughly. Potassium carbonate (0.15 g, 1.10 mmol) and tetrabutylammonium iodide (0.20 g, 0.55 mmol) were then added, in that order, and the reaction was allowed to proceed at room temperature for 3 hours. The reaction was monitored by TLC and LCMS. Upon completion, the mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give compound A-1-10-1-7 (0.15 g, 0.35 mmol, 64% yield). MS-ESI: [M+H] + =429.0 1 H NMR(400MHz,DMSO-d6)δ 8.80(td,J=2.9,1.2Hz,1H),7.77-7.67(m,2H),7.60(d,J=4.5Hz,1H),7.56(dd,J=8.6,6.1Hz,1H),7.47-7.37(m,1H),7.00(dd,J=7 .5,2.4Hz,1H),6.96(d,J=9.3Hz,1H),6.92-6.85(m,1H),6.33(d,J=1.0Hz,1H),6.00(t,J=6.8Hz,1H),1.60(dd,J=6.7,0.9Hz,3H).

[0304] [Production Example (3) 45: Compound A-1-10-1-47] [ka] In step 1, in a dry 50 mL three-neck flask, A-1-10-1-47a (15.00 g, 65.42 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (29.85 g, 78.50 mmol), triethylamine (16.55 g, 163.55 mmol), methoxymethylamine hydrochloride (7.02 g, 71.96 mmol), ) was added to 200 mL of dichloromethane and stirred overnight at room temperature. When TLC showed that the raw materials had completely reacted, the mixture was first washed with 1.0 M hydrochloric acid (200 mL), then with 0.5% aqueous sodium carbonate (150 mL), and then with water. After drying over anhydrous sodium sulfate, the mixture was concentrated and chromatographed to obtain compound A-1-10-1-47b (16.00 g, 58.75 mmol, yield 90%).

[0305] In step 2, compound A-1-10-1-47b (16.00 g, 58.75 mmol) was added to a dry 50 mL three-neck flask, followed by tetrahydrofuran (100 mL). The temperature was cooled to -10 °C, and 50 mL of ethylmagnesium bromide (2.0 M) was slowly added dropwise. The temperature was maintained for 30 minutes, then slowly raised to room temperature. TLC showed the raw material was consumed. 50 mL of ethyl acetate and 5% ammonium chloride solution (50 mL) were added. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give A-1-10-1-47c (10.00 g, 41.44 mmol, 71% yield).

[0306] In step 3, A-1-10-1-47c (10.00 g, 41.44 mmol) and tribromopyridine (19.88 g, 62.16 mmol) were added to 150 mL of tetrahydrofuran in a dry 50 mL three-neck flask. Protected with nitrogen, the mixture was heated to 60 °C. Upon the disappearance of the starting material as detected by TLC, ethyl acetate (100 mL) and 5% sodium dithionite solution (100 mL) were added. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give A-1-10-1-47d (6.73 g, 21.02 mmol, 51% yield).

[0307] In step 4, compound A-1-10-1-47d (6.73 g, 21.02 mmol) and A1-1-1c (5.49 g, 18.92 mmol) were added to a 100 mL three-neck flask in a dry 50 mL three-neck flask. After acetone (50 mL) was added and fully dissolved, potassium carbonate (5.81 g, 42.04 mmol) and tetrabutylammonium iodide (7.76 g, 21.02 mmol) were added in that order and the reaction was allowed to proceed at room temperature for 3 hours. After completion of the reaction, the reaction mixture was monitored by TLC and LCMS. The mixture was diluted with water and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give compound A-1-10-1-47e (2.68 g, 5.06 mmol, 24% yield).

[0308] In step 5, compound A-1-10-1-47e (2.68 g, 5.06 mmol) and ethyl acetate (50 mL) were added to a 100 mL three-neck flask in a dry 50 mL three-neck flask, followed by the addition of 10 mL of hydrogen chloride in dioxane (4.0 M). The mixture was heated to 50 °C and monitored by TLC. Once the starting materials were completely reacted, the mixture was cooled to 0 °C and filtered to obtain the hydrochloride salt of A-1-10-1-47f (2.00 g, 4.66 mmol, 85% yield). MS-ESI: [M+H] + =430.1

[0309] In step 6, compound A-1-10-1-47f (0.10 g, 0.22 mmol), potassium carbonate (0.15 g, 1.1 mmol), and dichloromethane (5 mL) were added to a dry 50 mL three-neck flask and stirred at room temperature for 2 hours. The mixture was filtered and concentrated, and the crude product was purified by flash chromatography to give compound A-1-10-1-47 (0.08 g, 0.19 mmol, 87% yield). MS-ESI: [M+H] + =430.1 1 H NMR(400MHz,DMSO-d6)δ 7.71(dd,J=8.9,2.2Hz,1H),7.56(dd,J=8.6,6.1Hz,1H),7.44(t,J=9.1,7.9Hz,1H ),7.02(dd,J=6.0,2.4Hz,1H),6.95(d,J=9.0Hz,1H),6.87(ddd,J=8.9,6.5,2.4Hz ,1H),6.33(s,1H),5.40(qd,J=6.6,2.9Hz,1H),3.22-2.95(m,4H),2.82-2.67(m,2 H),2.01(d,1H),1.69(d,J=12.1Hz,1H),1.61-1.50(m,2H),1.48(d,J=6.7Hz,3H).

[0310] [Production Example (3) 46: Compound A-1-2-1-104] [ka] In step 1, A-1-2-1-104a (800.0 mg, 4.90 mmol) and 2-bromopropanoic acid chloride (1.68 g, 9.80 mmol) were dissolved in dichloromethane (10 mL) in a 100 mL single-neck flask. Anhydrous aluminum chloride (1.96 g, 14.70 mmol) was slowly added to the solution at 0 °C. Once all the starting materials were added, the reaction was allowed to proceed at 40 °C for 1 hour. LCMS monitoring indicated complete reaction. The reaction was quenched by adding water (100 mL), extracted with ethyl acetate (50 mL × 3), and the combined organic layer was washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash chromatography to give compound A-1-2-1-104b (700.0 mg, 2.35 mmol, 48% yield). MS-ESI: [M+H] + =298.0

[0311] In step 2, intermediate A-1-2-1-104b (650.0 mg, 2.18 mmol), intermediate A1-1-1c (506.0 mg, 1.74 mmol), tetrabutylammonium iodide (1.21 g, 3.27 mmol), potassium carbonate (603.0 mg, 4.36 mmol), and N,N-dimethylformamide (10 mL) were added to a 100 mL single-neck flask in this order. After all the starting materials were added, the reaction mixture was allowed to react at room temperature for 3 hours. LCMS monitoring indicated complete reaction. The reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by flash chromatography to give compound A-1-2-1-104 (200.0 mg, 0.39 mmol, 18% yield). MS-ESI: [M+H] + 508.1 1H NMR(400MHz,DMSO-d6)δ 8.03(d,J=7.8Hz,2H),7.95(t,J=5.7Hz,1H),7.68(ddd,J=10.6,5.2,2.7Hz,1H),7 .54(dd,J=8.5,5.9Hz,1H),7.42(d,J=8.3Hz,3H),6.98(dd,J=6.6,2.4Hz,1H),6.93 (d,J=8.9Hz,1H),6.90-6.84(m,1H),6.30(q,J=1.2Hz,1H),6.23(qd,J=6.7,4.6Hz ,1H),3.33-3.26(m,2H),2.80(t,J=7.2Hz,2H),1.78(s,3H),1.56(d,J=6.6Hz,3H).

[0312] [Production Example (3) 47: Compound A-1-2-1-98] [ka] In step 1, diethyl carbonate (17.61 g, 149.04 mmol) was added to a dry 250 mL three-neck flask, and tetrahydrofuran (50 mL) was added to dissolve the mixture. The atmosphere was then purged with nitrogen. The reaction apparatus was placed in a low-temperature reaction vessel and cooled to 0 °C. Sodium hydride (2.98 g, 74.52 mmol) was added in several portions and allowed to react for 1 hour. Next, A-1-2-1-98a (5.00 g, 37.26 mmol) was added to the flask. The temperature was then slowly raised to room temperature, and the reaction time was 2 hours (preferably 2 to 4 hours). When TLC showed the reaction was complete, the mixture was quenched with 1 M hydrochloric acid solution at 0 °C until the pH reached 1. The temperature was controlled so that the temperature did not exceed 10 °C. The reaction mixture was extracted with ethyl acetate (100 mL × 3), the layers were separated, and the organic phases were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and rotary evaporated to give the crude intermediate A-1-2-1-98b (6.00 g, 33.94 mmol, 54.7% yield).

[0313] In step 2, A-1-2-1-98b (6.00 g, 20.36 mmol) and resorcinol (2.24 g, 20.36 mmol) were dissolved in methanesulfonic acid (30 mL) in a dry 250 mL three-neck flask, and the mixture was heated to 50 °C and reacted for 4 hours (preferably 4 to 8 hours). When LCMS showed the reaction was complete, the reaction mixture was slowly added to ethanol (100 mL) to control the quench temperature. The reaction mixture was then added to water (100 mL), extracted with ethyl acetate (200 mL x 3), and the layers were separated. The combined organic phases were washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, and rotary evaporated to give the crude intermediate A-1-2-1-98c (5.50 g, 21.80 mmol, 91% yield). MS-ESI: [M+H] + =253.2 1 H NMR(400MHz,DMSO-d6)δ 7.41-7.31(m,3H),7.21(d,J=7.7Hz,1H),6.83-6.77(m,2H),6.72(dd,J=8.7,2.2Hz,1H),6.07(d,J=1.9Hz,1H),2.09(s,3H).

[0314] In step 3, A-1-2-1-98c (1.61 g, 6.39 mmol), A-1-2-1-1d (2.00 g, 6.39 mmol), potassium carbonate (1.77 g, 12.78 mmol), and tetrabutylammonium iodide (2.36 g, 6.39 mmol) were added to a dry 100 mL three-neck flask in this order, dissolved in acetone (30 mL), and stirred at room temperature for 8 hours (preferably 8 to 12 hours) to react. LCMS showed that the reaction was complete, and the insoluble matter was filtered off, the solvent was removed by spin drying, water (30 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3), and the layers were separated. The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain intermediate A-1-2-1-98d (0.50 g, 1.03 mmol, yield 16.20%). MS-ESI:[M- t Bu]+ =429.2

[0315] In step 4, A-1-2-1-98d (0.50 g, 1.03 mmol) was dissolved in dichloromethane (10 mL) in a dry 100 mL three-neck flask, trifluoroacetic acid (10 mL) was added, and the mixture was stirred and reacted for 4 hours (preferably 4 to 8 hours). LCMS showed the reaction was complete, and the solvent was removed by spin drying. The product A-1-2-1-98 (335.30 mg, 0.78 mmol, 75.0% yield) was obtained by silica gel column chromatography (PE:EA = 2:1). MS-ESI:[MH] - =427.2 1 H NMR(400MHz,chloroform-d)δ 8.79(t,J=1.7Hz,1H),8.36(dq,J=7.8,1.5Hz,1H),8.29(dq,J=7.9,1.5Hz, 1H),7.65(td,J=7.8,1.8Hz,1H),7.37(td,J=7.5,1.5Hz,1H),7.32-7.27(m ,2H),7.15-7.10(m,1H),6.94(dd,J=8.7,0.9Hz,1H),6.87-6.60(m,2H),6. 15(s,1H),5.63(dd,J=6.9,4.4Hz,1H),2.13(s,3H),1.79(d,J=6.9Hz,3H).

[0316] [Production Example (3) 48: Compound A-1-2-1-99] [ka] In step 1, diethyl carbonate (17.61 g, 149.04 mmol) was added to a dry 250 mL three-neck flask, and tetrahydrofuran (50 mL) was added to dissolve the mixture. The mixture was then purged with nitrogen. The reaction apparatus was placed in a low-temperature reaction vessel and cooled to 0 °C. Sodium hydride (2.98 g, 74.52 mmol) was added in several portions and allowed to react for 1 hour. Next, A-1-2-1-99a (5.00 g, 37.26 mmol) was added to the flask. The temperature was then slowly raised to room temperature, and the reaction time was 2 hours (preferably 2 to 4 hours). When TLC showed the reaction was complete, the mixture was quenched with 1 M hydrochloric acid solution at 0 °C until the pH reached 1. The temperature was controlled so that the temperature did not exceed 10 °C. The reaction mixture was extracted with ethyl acetate (100 mL × 3), the layers were separated, and the organic phases were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and rotary evaporated to give the crude intermediate A-1-2-1-99b (7.00 g, 33.94 mmol, 91.1% yield).

[0317] In step 2, A-1-2-1-99b (6.00 g, 33.94 mmol) and resorcinol (3.74 g, 19.98 mmol) were dissolved in methanesulfonic acid (30 mL) in a dry 100 mL three-neck flask, and the mixture was heated to 50 °C and reacted for 4 hours (preferably 4 to 8 hours). When LCMS showed the reaction was complete, the reaction mixture was slowly added to ethanol (100 mL) to control the quench temperature. The reaction mixture was then added to water (100 mL), extracted with ethyl acetate (200 mL x 3), and the layers were separated. The combined organic phases were washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, and rotary evaporated to give the crude intermediate A-1-2-1-99c (5.50 g, 11.71 mmol, 54.6% yield). MS-ESI: [M+H] + =253.2

[0318] In step 3, A-1-2-1-99c (1.61 g, 6.39 mmol), A-1-2-1-98c (2.00 g, 6.39 mmol), potassium carbonate (1.77 g, 12.78 mmol), and tetrabutylammonium iodide (2.36 g, 6.39 mmol) were added to a dry 100 mL three-neck flask in this order, dissolved in acetone (30 mL), and stirred at room temperature for 8 hours (preferably 8 to 12 hours) to react. LCMS showed that the reaction was complete, and the insoluble matter was filtered off, the solvent was removed by spin drying, water (30 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3), and the layers were separated. The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain intermediate A-1-2-1-99d (0.35 g, 0.72 mmol, yield 11.31%). MS-ESI:[M- t Bu] + =429.2

[0319] In step 4, A-1-2-1-99d (0.35 g, 0.72 mmol) was added to a dry 50 mL three-neck flask, dissolved in dichloromethane (10 mL), and trifluoroacetic acid (10 mL) was added. The mixture was stirred and reacted for 4 hours (preferably 4 to 8 hours). LCMS showed the reaction was complete. The solvent was removed by spin drying, and the mixture was purified by silica gel column chromatography (PE:EA = 2:1) to give the product A-1-2-1-99 (238.60 mg, 0.56 mmol, 74.0% yield). MS-ESI:[MH] - =427.2 1H NMR(400MHz,chloroform-d)δ 8.80(t,J=1.8Hz,1H),8.36(dt,J=7.7,1.4Hz,1H),8.30(dt,J=7.9,1.5Hz,1H),7.65(t,J=7.8Hz,1H),7.41(d,J=8 .7Hz,1H),7.30(s,4H),6.86-6.76(m,2H),6.20(s,1H),5.64(d,J=6.9Hz,1H),2.43(s,3H),1.80(d,J=6.9Hz,3H).

[0320] [Production Example (3) 49: Compound A-1-2-1-100] [ka] In step 1, diethyl carbonate (8.80 g, 74.52 mmol) was added to a dry 100 mL three-neck flask, and tetrahydrofuran (50 mL) was added to dissolve the mixture. The flask was then purged with nitrogen. The reaction apparatus was placed in a low-temperature reaction vessel and cooled to 0 °C. Sodium hydride (1.49 g, 37.26 mmol) was added in several portions and reacted for 1 hour. Next, A-1-2-1-100a (2.50 g, 18.63 mmol) was added to the flask. The temperature was then slowly raised to room temperature, and the reaction time was 2 hours (preferably 2 to 4 hours). When TLC showed the reaction was complete, the mixture was quenched with 1 M hydrochloric acid solution at 0 °C until the pH reached 1. The temperature was controlled so that the temperature did not exceed 10 °C. The reaction mixture was extracted with ethyl acetate (100 mL × 3), the layers were separated, and the organic phases were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and rotary evaporated to give the crude intermediate A-1-2-1-100b (3.00 g, 33.94 mmol, 78.1% yield).

[0321] In step 2, A-1-2-1-100b (3.00 g, 14.55 mmol) and resorcinol (1.60 g, 14.55 mmol) were dissolved in methanesulfonic acid (30 mL) in a dry 100 mL three-neck flask, and the mixture was heated to 50 °C and reacted for 4 hours (preferably 4 to 8 hours). When LCMS showed the reaction was complete, the reaction mixture was slowly added to ethanol (100 mL) to control the quench temperature. The reaction mixture was then added to water (100 mL), extracted with ethyl acetate (200 mL x 3), and the layers were separated. The combined organic phases were washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, and rotary evaporated to give the crude intermediate A-1-2-1-100c (3.50 g, 13.88 mmol, 81.1% yield). MS-ESI: [M+H] + =253.2 1 H NMR(400MHz,DMSO-d6)δ 7.41-7.31(m,3H),7.21(d,J=7.7Hz,1H),6.83-6.77(m,2H),6.72(dd,J=8.7,2.2Hz,1H),6.07(d,J=1.9Hz,1H),2.09(s,3H).

[0322] In step 3, A-1-2-1-100c (1.61 g, 6.39 mmol), A1-2-1-98c (2.00 g, 6.39 mmol), potassium carbonate (1.77 g, 12.78 mmol), and tetrabutylammonium iodide (2.36 g, 6.39 mmol) were added to a dry 100 mL three-neck flask in this order, dissolved in acetone (30 mL), and stirred at room temperature for 8 hours (preferably 8 to 12 hours) to react. LCMS showed that the reaction was complete, and the insoluble matter was filtered off, the solvent was removed by spin drying, water (30 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3), and the layers were separated. The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain intermediate A-1-2-1-100d (0.60 g, 1.24 mmol, yield 19.40%). MS-ESI:[M- t Bu]+ =429.2

[0323] In step 4, A-1-2-1-100d (0.60 g, 1.24 mmol) was dissolved in dichloromethane (10 mL) in a dry 50 mL three-neck flask, trifluoroacetic acid (10 mL) was added, and the mixture was stirred and reacted for 4 hours (preferably 4 to 8 hours). LCMS showed the reaction was complete, and the solvent was removed by spin drying. The product was purified by silica gel column chromatography (PE:EA = 2:1) to give product A-1-2-1-100 (331.6 mg, 0.77 mmol, 60.0% yield). MS-ESI:[MH] - =427.2 1 H NMR(400MHz,chloroform-d)δ 8.80(t,J=1.8Hz,1H),8.36(dt,J=7.8,1.4Hz,1H),8.30(dt,J=7.9,1.5Hz,1H),7.65(t,J=7.8Hz,1H),7.43-7.32(m,2H),7.3 2-7.28(m,1H),7.21-7.14(m,2H),6.89-6.76(m,2H),6.20(s,1H),5.64(q,J=6.9Hz,1H),2.41(s,3H),1.80(d,J=6.9Hz,3H).

[0324] [Production example (3) 50: Compound A-1-2-1-101] [ka] In step 1, diethyl carbonate (11.87 g, 100.48 mmol) was added to a dry 100 mL three-neck flask, and tetrahydrofuran (50 mL) was added to dissolve the mixture. The atmosphere was then purged with nitrogen. The reaction apparatus was placed in a low-temperature reaction vessel and cooled to 0 °C. Sodium hydride (2.01 g, 50.24 mmol) was added in several portions and allowed to react for 1 hour. Next, A-1-2-1-101a (5.00 g, 25.12 mmol) was added to the flask. The temperature was then slowly raised to room temperature, and the reaction time was 2 hours (preferably 2 to 4 hours). When TLC showed the reaction was complete, the mixture was quenched with 1 M hydrochloric acid solution at 0 °C until the pH reached 1. The temperature was controlled so that the temperature did not exceed 10 °C. The reaction mixture was extracted with ethyl acetate (100 mL × 3), the layers were separated, and the organic phases were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and rotary evaporated to give the crude intermediate A-1-2-1-101b (6.50 g, 23.98 mmol, yield 95.44%). MS-ESI:[MH] - =268.9

[0325] In step 2, A-1-2-1-101b (6.50 g, 23.98 mmol) and resorcinol (2.64 g, 23.98 mmol) were dissolved in methanesulfonic acid (30 mL) in a dry 100 mL three-neck flask, and the mixture was heated to 50 °C and reacted for 4 hours (preferably 4 to 8 hours). When LCMS showed the reaction was complete, the reaction mixture was slowly added to ethanol (100 mL) to control the quench temperature. The reaction mixture was then added to water (100 mL), extracted with ethyl acetate (200 mL x 3), and the layers were separated. The combined organic phases were washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, and rotary evaporated to give the crude intermediate A-1-2-1-101c (7.20 g, 19.30 mmol, 80.49% yield). MS-ESI:[MH] - =314.9

[0326] In step 3, A-1-2-1-101c (2.00 g, 6.31 mmol), ethylboronic acid (2.33 g, 31.55 mmol), and potassium phosphate (4.02 g, 18.93 mmol) were added to a dry 100 mL three-neck flask in this order and dissolved in 20 mL of toluene and 4 mL of water. The atmosphere was purged with nitrogen, and palladium acetate (0.071 g, 0.32 mmol) and tricyclohexylphosphine (0.18 g, 0.63 mmol) were added, followed by a reaction at 100°C for 6 hours (preferably 6 to 8 hours). LCMS showed that the reaction was complete, and the insoluble matter was filtered off, the solvent was removed by spin drying, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3), and the layers were separated. The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain intermediate A-1-2-1-101d (1.15 g, 4.31 mmol, yield 68.48%). MS-ESI:[MH] - =265.1

[0327] In step 4, A-1-2-1-101d (1.15 g, 4.31 mmol) and A1-2-1-98c (1.50 g, 4.79 mmol) were added in this order to a dry 100 mL three-neck flask and dissolved in 10 mL of acetone, and tetrabutylammonium iodide (1.77 g, 4.79 mmol) and potassium carbonate (1.32 g, 9.58 mmol) were added and stirred to disperse the mixture, and the mixture was stirred at room temperature for 8 hours (preferably 8 to 12 hours) to react. When LCMS showed that the reaction was complete, the insoluble matter was filtered off, the solvent was removed by spin drying, water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3), and the layers were separated. The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1) to give intermediate A-1-2-1-101e (580.0 mg, 1.16 mmol, yield 24.29%). MS-ESI:[MH] - =497.2

[0328] In step 5, A-1-2-1-101e (580.0 mg, 1.16 mmol) was dissolved in dichloromethane (10 mL) in a dry 50 mL three-neck flask, trifluoroacetic acid (10 mL) was added, and the mixture was stirred for 4 hours (preferably 4-8 hours). LCMS showed the reaction was complete, and the solvent was removed by spin drying. The product A-1-2-1-101 was purified by silica gel column chromatography (PE:EA = 2:1) to give the product A-1-2-1-101 (336.2 mg, 0.76 mmol, 36.27% yield). MS-ESI:[MH] - =441.2 1 H NMR (400 MHz, chloroform-d) δ 8.79 (t, J = 1.6 Hz, 1H), 8.36 (dq, J = 7.8, 1.6 Hz, 1H), 8.33-8.26 (m, 1H), 7.65 (td, J = 7.8, 2.1 Hz, 1H), 7.41 (td, J = 7.5, 1.4 Hz, 1H), 7.35 (dd, J = 7.8, 1.4 Hz, 1H), 7.30-7.24 (m, 1 H),7.10(dt,J=7.6,1.6Hz,1H),6.94(dd,J=8.8,1.4Hz,1H),6.81-6.72(m,2H),6.17( s,1H),5.66-5.53(m,1H),2.54-2.27(m,2H),1.79(d,J=6.8Hz,3H),1.14-0.95(m,3H).

[0329] [Production example (3) 51: Compound A-1-2-1-102] [ka] In step 1, diethyl carbonate (11.87 g, 100.48 mmol) was added to a dry 100 mL three-neck flask, and tetrahydrofuran (50 mL) was added to dissolve the mixture. The atmosphere was then purged with nitrogen. The reaction apparatus was placed in a low-temperature reaction vessel and cooled to 0 °C. Sodium hydride (2.01 g, 50.24 mmol) was added in several portions and allowed to react for 1 hour. Next, A-1-2-1-102a (5.00 g, 25.12 mmol) was added to the flask. The temperature was then slowly raised to room temperature, and the reaction time was 2 hours (preferably 2 to 4 hours). When TLC showed the reaction was complete, the mixture was quenched with 1 M hydrochloric acid solution at 0 °C until the pH reached 1. The temperature was controlled so that the temperature did not exceed 10 °C. The reaction mixture was extracted with ethyl acetate (100 mL × 3), the layers were separated, and the organic phases were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and rotary evaporated to give the crude intermediate A-1-2-1-102b (6.50 g, 23.98 mmol, yield 95.44%). MS-ESI:[MH] - =268.9

[0330] In step 2, A-1-2-1-102b (6.50 g, 23.98 mmol) and resorcinol (2.64 g, 23.98 mmol) were dissolved in methanesulfonic acid (30 mL) in a dry 100 mL three-neck flask, and the mixture was heated to 50 °C and reacted for 4 hours (preferably 4 to 8 hours). When LCMS showed the reaction was complete, the reaction mixture was slowly added to ethanol (100 mL) to control the quench temperature. The reaction mixture was then added to water (100 mL), extracted with ethyl acetate (200 mL x 3), and the layers were separated. The combined organic phases were washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, and rotary evaporated to give the crude intermediate A-1-2-1-102c (7.20 g, 19.30 mmol, 80.49% yield). MS-ESI:[MH] - =314.9

[0331] In step 3, A-1-2-1-102c (4.00 g, 12.61 mmol), cyclopropylboronic acid (15.13 g, 7.57 mmol), and potassium phosphate (8.03 g, 37.83 mmol) were added to a dry 100 mL three-neck flask in this order and dissolved in 40 mL of toluene and 8 mL of water. The flask was purged with nitrogen, and palladium acetate (0.14 g, 0.63 mmol) and tricyclohexylphosphine (0.35 g, 1.26 mmol) were added, followed by a reaction at 100°C for 6 hours. LCMS showed that the reaction was complete, and the insoluble matter was filtered off, the solvent was removed by spin drying, water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3), and the layers were separated. The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain intermediate A-1-2-1-102d (1.75 g, 5.75 mmol, yield 48.43%). MS-ESI:[MH] - =277.0

[0332] In step 4, in a dry 100 mL three-neck flask, tert-butyl 3-(2-bromopropionyl)benzoate (2.50 g, 7.98 mmol) was dissolved in 20 mL of acetone, tetrabutylammonium iodide (2.95 g, 7.98 mmol) and potassium carbonate (2.21 g, 15.96 mmol) were added and stirred to disperse, and finally, A-1-2-1-102d (1.75 g, 6.29 mmol) was added and stirred at room temperature to react, and the mixture was stirred at room temperature for 8 hours (preferably 8 to 12 hours). LCMS showed that the reaction was complete, and the insoluble matter was filtered off, the solvent was removed by spin drying, water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3), and the layers were separated. The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1) to give intermediate A-1-2-1-102e (1.30 g, 2.55 mmol, yield 31.90%). MS-ESI:[M- t Bu] + =455.2

[0333] In step 5, A-1-2-1-102e (1.30 g, 2.55 mmol) was dissolved in dichloromethane (10 mL) in a dry 100 mL three-neck flask, trifluoroacetic acid (10 mL) was added, and the mixture was stirred and reacted for 4 hours (preferably 4-8 hours). LCMS showed the reaction was complete, and the solvent was removed by spin drying. The product A-1-2-1-102 was purified by silica gel column chromatography (PE:EA = 2:1) to give the product A-1-2-1-102 (679.3 mg, 1.38 mmol, 54.33% yield). MS-ESI: [M+H] + =455.2 1 H NMR (400 MHz, chloroform-d) δ 8.79 (d, J = 1.7 Hz, 1H), 8.36 (dt, J = 7.7, 1.4 Hz, 1H), 8.30 (dt, J = 7.8, 1.5 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.42-7.29 (m, 2H), 7.19-7.12 (m, 2H), 7.09 (t, J = 1.8 Hz, 1H) ),6.85-6.77(m,2H),6.19(s,1H),5.63(d,J=6.9Hz,1H),1.94(ddd,J=8.5,5.1,3 .4Hz,1H),1.80(d,J=6.8Hz,3H),1.08-0.95(m,2H),0.72(dt,J=6.7,4.7Hz,2H).

[0334] [Production Example (3) 52: Compound A-1-2-1-103] [ka] In step 1, diethyl carbonate (11.87 g, 100.48 mmol) was added to a dry 100 mL three-neck flask, and tetrahydrofuran (50 mL) was added to dissolve the mixture. The mixture was then purged with nitrogen. The reaction apparatus was placed in a low-temperature reaction vessel and cooled to 0 °C. Sodium hydride (2.01 g, 50.24 mmol) was added in several portions and allowed to react for 1 hour. Next, A-1-2-1-103a (5.00 g, 25.12 mmol) was added to the flask. The temperature was then slowly raised to room temperature, and the reaction time was 2 hours (preferably 2 to 4 hours). When TLC showed the reaction was complete, the mixture was quenched with 1 M hydrochloric acid solution at 0 °C until the pH reached 1. The temperature was controlled so that the temperature did not exceed 10 °C. The reaction mixture was extracted with ethyl acetate (100 mL × 3), the layers were separated, and the organic phases were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and rotary evaporated to give the crude intermediate A-1-2-1-103b (6.50 g, 23.98 mmol, yield 95.44%). MS-ESI:[MH] - =268.9

[0335] In step 2, A-1-2-1-103b (6.50 g, 23.98 mmol) and resorcinol (2.64 g, 23.98 mmol) were dissolved in methanesulfonic acid (30 mL) in a dry 100 mL three-neck flask, and the mixture was heated to 50 °C and reacted for 4 hours (preferably 4 to 8 hours). When LCMS showed the reaction was complete, the reaction mixture was slowly added to ethanol (100 mL) to control the quench temperature. The reaction mixture was then added to water (100 mL), extracted with ethyl acetate (200 mL x 3), and the layers were separated. The combined organic phases were washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, and rotary evaporated to give the crude intermediate A-1-2-1-103c (7.20 g, 19.30 mmol, 80.49% yield). MS-ESI:[MH] - =314.9

[0336] In step 3, A-1-2-1-103c (2.00 g, 6.31 mmol), palladium acetate (0.071 g, 0.32 mmol), triphenylphosphine (0.17 g, 0.63 mmol), dicesium carbonate (6.17 g, 18.93 mmol), and potassium vinyltrifluoroborate (1.27 g, 9.46 mmol) were added to a dry 100 mL three-neck flask in this order, the atmosphere was replaced with nitrogen, the mixture was dissolved in 20 mL of dioxane and 2 mL of water, and the mixture was reacted at 100°C for 6 hours (preferably 6 to 8 hours). LCMS showed the reaction was complete, the insoluble matter was filtered off, the solvent was removed by spin drying, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3), and the layers were separated. The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain intermediate A-1-2-1-103d (1.30 g, 4.60 mmol, yield 54.90%).

[0337] In step 4, A-1-2-1-103d (1.22 g, 4.60 mmol) and A-1-2-1-1d (1.60 g, 5.11 mmol) were added in this order to a dry 100 mL three-neck flask and dissolved in 20 mL of acetone, and tetrabutylammonium iodide (1.89 g, 5.11 mmol) and potassium carbonate (1.41 g, 10.22 mmol) were added and stirred to disperse, and the mixture was stirred at room temperature for 8 hours (preferably 8 to 12 hours) to react. When LCMS showed that the reaction was complete, the insoluble matter was filtered off, the solvent was removed by spin drying, water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3), and the layers were separated. The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1) to give intermediate A-1-2-1-103e (860.0 mg, 1.73 mmol, yield 33.90%). MS-ESI:[MH] - =495.2

[0338] In step 5, A-1-2-1-103e (860.0 mg, 1.73 mmol) was dissolved in dichloromethane (10 mL) in a dry 50 mL three-neck flask, trifluoroacetic acid (10 mL) was added, and the mixture was stirred and reacted for 4 hours (preferably 4-8 hours). LCMS showed the reaction was complete, and the solvent was removed by spin drying. The product A-1-2-1-103 was purified by silica gel column chromatography (PE:EA = 2:1) to give the product A-1-2-1-103 (383.0 mg, 0.87 mmol, 41.22% yield). MS-ESI:[MH] - =439.2 1 H NMR (400 MHz, chloroform-d) δ 8.79 (t, J = 1.7 Hz, 1H), 8.36 (dq, J = 7.8, 1.6 Hz, 1H), 8.32-8.26 (m, 1H), 7.72-7.63 (m, 2H), 7.45 (td, J = 7.7, 1.5 Hz, 1H), 7.36 (tt, J = 7.4, 1.0 Hz, 1H), 7.17 (dt, J = 7.5, 1.6 Hz, 1H) ),7.02-6.94(m,1H),6.83-6.71(m,2H),6.51-6.33(m,1H),6.17(s,1H),5.71(dd,J=17 .3,1.0Hz,1H),5.65-5.57(m,1H),5.18(dd,J=10.9,1.0Hz,1H),1.79(d,J=6.9Hz,3H).

[0339] [Production Example (3) 53: Compound A-1-2-2-2] [ka] In step 1, compound A-1-2-2-2a (5.00 g, 36.2 mmol) and phenylacetyl chloride (6.16 g, 39.8 mmol, 5.31 mL) were dissolved in acetone (360 mL) in a dry 100 mL three-neck flask. Potassium carbonate (17.5 g, 126 mmol) was added at 25 °C, and the mixture was stirred at 60 °C for 6 h. The progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction solution was poured into water (300 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was used directly in the next step. Compound A-1-2-2-2b (7.26 g, 29.7 mmol, 82.1% yield, 97.5% purity) was obtained as a yellow solid. MS-ESI: [M+H] + =239.1 1 H NMR(400MHz,DMSO-d6)δ 10.61(br s,1H),8.15(s,1H),7.71-7.69(m,1H),7.68(s,1H),7.60(d,J=8.4Hz,1H),7.46-7 .41(m,2H),7.40-7.35(m,1H),6.82(dd,J=2.4,8.8Hz,1H),6.76(d,J=2.4Hz,1H).

[0340] In step 2, compound A-1-2-2-2b (1.50 g, 6.14 mmol, 97.5%) and methyl 2-bromopropionate (1.23 g, 7.37 mmol) were dissolved in N,N-dimethylformamide (15 mL) in a dry 100 mL three-neck flask. Dicesium carbonate (4.00 g, 12.3 mmol) was added at 25 °C, and the mixture was stirred at 70 °C for 2 h. The reaction progress was monitored by LCMS. After completion of the reaction, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was used directly in the next step. Compound A-1-2-2-2c (1.77 g, 5.24 mmol, 85.3% yield, 96.0% purity) was obtained as a yellow solid. MS-ESI: [M+H] + =325.0 1 H NMR(400MHz,DMSO-d6)δ 8.20(s,1H),7.72-7.69(m,3H),7.48-7.37(m,3H),6.98(dd,J=2.4,4.4Hz,2H),5.24(q,J=6.8Hz,1H),3.70(s,3H),1.56(d,J=6.8Hz,3H).

[0341] In step 3, compound A-1-2-2-2c (1.77 g, 5.24 mmol, purity 96.0%) was dissolved in tetrahydrofuran (90 mL) and water (30 mL) in a dry 100 mL three-neck flask. Lithium hydroxide monohydrate (219.0 mg, 5.24 mmol, 1.00 eq) was added at 0 °C, and the mixture was stirred at 0 °C for 2 h. The reaction progress was monitored by LCMS. After completion of the reaction, the pH of the mixture was adjusted to 8 with 1 M HCl, and then the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (HCl). Compound A-1-2-2-2d (200.0 mg, 524 μmol, yield 10.0%, purity 81.3%) was obtained as a white solid. MS-ESI: [M+H] + =311.1

[0342] In step 4, compound A-1-2-2-2d (200.0 mg, 524 μmol, purity 81.3%), 3-piperidinecarbonitrile (57.7.0 mg, 524 μmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (239.0 mg, 628 μmol), and N,N-diisopropylethylamine (101.0 mg, 786 μmol) were dissolved in N,N-dimethylformamide (2 mL) in a dry 100 mL three-neck flask. The mixture was stirred at 20 °C for 16 h. The reaction progress was monitored by LCMS. After completion of the reaction, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomene*C18 150 × 25 m × 10 μm, mobile phase: [water (ammonium bicarbonate)-acetonitrile], B%: 30%-60%, 8 min), and lyophilized to give A-1-2-2-2 (70.0 mg, 172 μmol, yield 32.8%, purity 99.0%) as a white solid. MS-ESI: [M+H] + =403.0

[0343] [Production Example (3) 54: Compound A-1-2-6-22] [ka] In step 1, compound A-1-2-6-22a (4.50 g, 23.4 mmol, 1.00 eq) was stirred in a solution of POBr (8.73 g, 30.4 mmol, 3.09 mL, 1.30 eq) in a dry 100 mL three-neck flask at 130 °C for 1 h. The reaction progress was monitored by LCMS. After the reaction was completed, the reaction mixture was cooled to 20 °C and poured into water (50 mL). The pH was adjusted to 9 with saturated aqueous sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The product was used directly in the next step. Compound A-1-2-6-22b (3.00 g, 7.47 mmol, 31.9% yield, 63.5% purity) was obtained as a yellow solid. MS-ESI: [M+H] + =254.8

[0344] In step 2, compound A-1-2-6-22b (3.00 g, 11.8 mmol, 1.00 eq) was added to a dry 100 mL three-neck flask and dissolved in dichloromethane (100 mL). The mixture was purged with nitrogen, and the reaction temperature was controlled to 20 °C. Boron tribromide (8.84 g, 35.3 mmol, 3.40 mL, 3.00 eq) was added and the mixture was stirred at 20 °C for 1 h. The reaction progress was monitored by LCMS. After the reaction was completed, the reaction mixture was poured into water (300 mL) at 20 °C. The pH was adjusted to 9 with saturated aqueous sodium bicarbonate solution, and the reaction mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was used directly in the next step. A yellow solid compound A-1-2-6-22c (2.70 g, 1.04 mmol, yield 8.83%, purity 9.27%) was obtained. MS-ESI: [M+H] + =240.8

[0345] In step 3, compound a-1-2-6-22c (2.54 g, 10.5 mmol, 1.00 eq), methyl 2-bromopropionate (1.85 g, 11.1 mmol, 1.23 mL, 1.05 eq), and dicesium carbonate (5.15 g, 15.8 mmol, 1.5 eq) were dissolved in N,N-dimethylformamide (26 mL) in a dry 100 mL three-neck flask, and the mixture was stirred at 20 °C for 2 h. The reaction progress was monitored by LCMS. After completion of the reaction, the reaction mixture was poured into water (100 mL). The reaction mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The product was used directly in the next step. A yellow solid compound A-1-2-6-22d (2.45 g, 4.28 mmol, yield 40.7%, purity 57.2%) was obtained. MS-ESI: [M+H] + =326.8

[0346] In step 4, compound A-1-2-6-22d (2.45 g, 7.49 mmol, 1.00 eq) was dissolved in hydrochloric acid solution (25 mL) (37% purity) in a dry 100 mL three-neck flask and stirred at 20 °C for 12 h. The reaction progress was monitored by LCMS. After the reaction was completed, the reaction mixture was poured into 1 M hydrochloric acid solution (100 mL) at 20 °C. The reaction mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was used directly in the next step. Compound A-1-2-6-22e (2.37 g, 4.97 mmol, 66.3% yield, 65.6% purity) was obtained as a yellow solid. MS-ESI: [M+H] + =312.8

[0347] In step 5, compound a-1-2-6-22e (150.0 mg, 479 μmol, 1.00 eq), tributyl(2-pyridyl)tin (229.0 mg, 621 μmol), cuprous iodide (45.6.0 mg, 240 μmol), and triphenylphosphine (25.1.0 mg, 95.8 μmol) were added to a dry 100 mL three-neck flask, and the flask was purged with nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (43.9.0 mg, 47.9 μmol) was then added, followed by dioxane (7 mL) as solvent. The mixture was again degassed in vacuo and purged with nitrogen three times and stirred at 50 °C for 12 h. The reaction progress was monitored by LCMS. After the reaction was completed, the mixture was cooled to 25°C, filtered through a Celite pad, and the filtrate was washed with ethyl acetate (10 mL). Water (30 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (10 mL). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was used directly in the next step. Compound A-1-2-6-22f (530.0 mg, crude product) was obtained as a yellow oil. MS-ESI: [M+H] + =311.9

[0348] In step 6, compound a-1-2-6-6-22f (530.0 mg, 1.70 mmol), 3-piperidinecarbonitrile (225.0 mg, 2.04 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (971.0 mg, 2.55 mmol, 1.50 eq) and N,N-diisopropylethylamine (440.0 mg, 3.41 mmol, 593 μL, 2.00 eq) were dissolved in N,N-diisopropylethylamine (5 mL) in a dry 100 mL three-neck flask and stirred at 20 °C for 1 h. The reaction progress was monitored by LCMS. After the reaction was completed, the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative HPLC (column: Phenomene*C18 250 × 50 mm × 10 μm, mobile phase: [water (ammonium bicarbonate)-acetonitrile], B%: 15%-4.6%, 9 min) to give A-1-2-6-22 (84.0 mg, 206 μmol, yield 12.1%, purity 99.0%) as a yellow solid. MS-ESI: [M+H] + =404.1 1 H NMR(400MHz,DMSO-d6)δ 8.78(d,J=4.0Hz,1H),8.11-7.94(m,1H),7.78(d,J=7.6Hz,1H),7.73-7. 65(m,1H),7.72-7.66(m,1H),7.03-6.91(m,1H),6.90-6.86(m,1H),6.44 (s,1H),5.63-5.53(m,1H),4.02-3.82(m,1H),3.80-3.63(m,1H),3.60-3 .46(m,2H),3.17-3.01(m,1H),1.89(d,J=4.8Hz,2H),1.68-1.43(m,5H).

[0349] [Production Example (3) 55: Compound A-1-2-6-23] [ka] In step 1, compound a-1-2-6-23a (600.0 mg, 1.92 mmol) and 3-pyridylboronic acid (283.0 mg, 2.30 mmol) were dissolved in a mixture of dioxane (6 mL) and water (2 mL) in a dry 100 mL three-neck flask. The mixture was then purged with nitrogen, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (140.0 mg, 192 μmol) and potassium acetate (376 mg, 3.83 mmol) were added. The mixture was again degassed and purged with nitrogen three times. The mixture was stirred at 90 °C for 1 h. The reaction progress was monitored by LCMS. After completion of the reaction, the mixture was cooled to 25 °C, filtered through a pad of Celite, and the filtrate was washed with ethyl acetate (10 mL). Water (30 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (10 mL). The combined organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated to give the crude product, which was used directly in the next step. A yellow oily compound A-1-2-6-23b (722.0 mg, 993 μmol, yield 51.8%, purity 42.8%) was obtained. MS-ESI: [M+H] + =311.8

[0350] In step 2, compound A-1-2-6-23b (722.0 mg, 2.32 mmol), 3-piperidinecarbonitrile (306.0 mg, 2.78 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.32 g, 3.48 mmol), and N,N-diisopropylethylamine (600.0 mg, 4.64 mmol) were dissolved in N,N-dimethylformamide (8 mL) in a dry 100 mL three-neck flask, and the mixture was stirred at 20 °C for 1 h. The reaction progress was monitored by LCMS. After completion of the reaction, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative HPLC (column: Phenomene*C18 250 × 50 mm × 10 μm, mobile phase: [water (ammonium bicarbonate)-acetonitrile], B%: 15%-45%, 8 min) to give an off-white solid A-1-2-6-23 (96.60 mg, 233 μmol, yield 10.0%, purity 97.1%). MS-ESI: [M+H] + =404.0 1 H NMR(400MHz,DMSO-d6)δ 8.81-8.67(m,2H),7.98(d,J=8.0Hz,1H),7.62-7.59(m,1H),7.36-7.19(m,1H),7.08-6.92(m,1H),6.88(d,J=8.8Hz,1H),6.37(s,1H) ,5.62-5.45(m,1H),4.04-3.83(m,1H),3.80-3.63(m,1H),3.59-3.37(m,2H),3.18-3.00(m,1H),2.02-1.79(m,2H),1.78-1.40(m,5H).

[0351] [Production Example (3) 56: Compound A-1-2-6-24] [ka] In step 1, compound a-1-2-6-24a (400 mg, 1.28 mmol) and 4-pyridylboronic acid (188.0 mg, 1.53 mmol, 1.20 eq) were dissolved in a mixture of dioxane (4.00 mL) and water (1.00 mL) in a dry 100 mL three-neck flask. The mixture was purged with nitrogen, and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (93.5 mg, 128 μmol) and potassium acetate (251 mg, 2.56 mmol) were added. The mixture was again degassed and purged with nitrogen three times. The mixture was stirred at 90 °C for 1 h. The reaction progress was monitored by LCMS. After the reaction was complete, the mixture was cooled to 25°C and poured into saturated ammonium chloride solution (20.0 mL) at 0-5°C. The mixture was extracted with ethyl acetate (10.0 mL x 3). The combined organic phases were washed with saturated brine (10.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was used directly in the next step. A yellow oily compound, A-1-2-6-24b (250.0 mg, 426 μmol, yield 33.3%, purity 53.0%), was obtained. MS-ESI: [M+H] + =311.9

[0352] In step 2, compound A-1-2-6-24b (247.0 mg, 793 μmol), 3-piperidinecarbonitrile (105.0 mg, 952 μmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (453.0 mg, 1.19 mmol), and N,N-diisopropylethylamine (205.0 mg, 1.59 mmol) were dissolved in N,N-dimethylformamide (2.50 mL) in a dry 100 mL three-neck flask. The mixture was stirred at 20 °C for 1 h. The reaction progress was monitored by LCMS. After completion of the reaction, the reaction mixture was poured into ice water (20.0 mL), the pH was adjusted to 8 with saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate (10.0 mL × 3). The combined organic phase was washed with saturated brine (10.0 mL × 2), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative HPLC (column: Waters*bridge 150 × 25 mm 10 μm, mobile phase: [water (ammonium bicarbonate)-acetonitrile], B%: 16%-46%, 8 min) to give compound A-1-2-6-24 (31.4 mg, 76.3 μmol, yield 9.61%, purity 98.0%). MS-ESI: [M+H] + =404.0 1 H NMR(400MHz,DMSO-d6)δ 8.81-8.73(m,2H),7.58-7.51(m,2H),7.31-7.20(m,1H),7.08-6.92(m,1H),6.91-6.81(m,1H),6.35(s,1H),5.59-5.46(m, 1H),4.03-3.83(m,1H),3.80-3.64(m,1H),3.56-3.35(m,2H),3.25-3.02(m,1H),1.89(d,J=4.8Hz,2H),1.76-1.41(m,5H).

[0353] [Production Example (3) 57: Compound A-7-1-1-1] [ka] In step 1, in a dry 100 mL three-neck flask, A-7-1-1-1a (444.0 mg, 5.15 mmol), triphenylphosphine (1.56 g, 5.95 mmol), and A-1-2-1-98c (1.00 g, 3.96 mmol, 1.00 eq) were dissolved in tetrahydrofuran (10 mL), purged with nitrogen, and diisopropyl azodicarboxylate (1.28 g, 6.34 mmol) was added dropwise at 0 °C, controlling the reaction temperature so that it did not exceed 5 °C. After the addition was complete, the mixture was stirred at 20 °C for 12 hours. The progress of the reaction was monitored by LCMS. After the reaction was completed, the reaction mixture was poured into saturated sodium sulfite solution (10 mL), the pH was adjusted to 9 using saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane (5 mL × 3). The combined organic phase was washed with saturated brine (5.00 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (silica gel, ethyl acetate:petroleum ether = 1:20 to 1:10) to obtain the product (petroleum ether:ethyl acetate = 10:1, R f =0.60) to give yellow compound A-7-1-1-1b (1.10 g, 3.43 mmol, yield 86.6%, purity 100%). MS-ESI: [M+H] + =321.1 1 H NMR(400MHz,DMSO-d6)δ 7.46-7.31(m,3H),7.24(d,J=7.6Hz,1H),7.09(s,1H),6.85(d,J=1.2Hz,2H),6.16(s,1H),5.84-5.7 9(m,1H),5.19-5.02(m,2H),4.72-4.67(m,1H),2.48-2.31(m,2H),2.11(s,3H)1.27(d,J=6.0Hz,3H).

[0354] In step 2, sodium periodate (3.30 g, 15.5 mmol) and ruthenium(III) chloride hydrate (15.5 mg, 68.7 μmol) were dissolved in a mixture of dichloromethane (2 mL), acetonitrile (2 mL), and water (6 mL) in a dry 100 mL three-neck flask. The mixture was cooled to 0 °C, and A-7-1-1-1b (1.10 g, 3.43 mmol) dissolved in dichloromethane (2 mL) and acetonitrile (2 mL) was added. The mixture was stirred at -5 to 0 °C for 3 h. The reaction progress was monitored by LCMS. After completion of the reaction, the mixture was poured into saturated sodium sulfite solution (30 mL), the pH was adjusted to 9 with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with dichloromethane (10 mL × 3). The combined organic phase was washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by pre-HPLC (column: Phenomene*Luna C18 200 × 40 mm × 10 μm, mobile phase: [water (hydrochloric acid) - acetonitrile], B%: 40% - 70%, 10 min) to obtain compound A-7-1-1-1c (70.0 mg, 203 μmol, yield 5.92%, purity 98.2%). MS-ESI: [M+H] + =339.0

[0355] In step 3, compound A-7-1-1-1c (70.0 mg, 207 μmol), dimethylamine (10.30 mg, 228 μmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (118.0 mg, 310 μmol), and N,N-diisopropylethylamine (80.2 mg, 621 μmol) were dissolved in N,N-dimethylformamide (1 mL) in a dry 100 mL three-neck flask and stirred at 20 °C for 1 h. The reaction progress was monitored by LCMS. After completion of the reaction, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative HPLC (column: Phenomene*Luna C18 150 × 25 mm × 10 μm, mobile phase: [water (hydrochloric acid)-acetonitrile], B%: 43%-72%, 10 min) to give a yellow solid A-7-1-1-1 (40.0 mg, 98.8 μmol, yield 47.7%, purity 95.8%). MS-ESI: [M+H] + =366.1 1 H NMR(400MHz,DMSO-d6)δ 7.48-7.30(m,3H),7.23(d,J=7.6Hz,1H),7.07-6.98(m,1H),6.90-6.77(m,2H),6.17(s,1H),5.06-4.93(m ,1H),2.98(s,3H),2.85-2.82(m,1H),2.80(s,3H),2.63-2.53(m,1H),2.12(s,3H),1.32(d,J=6.0Hz,3H).

[0356] [Production Example (3) 58: Compound A-7-1-1-2] [ka] In step 1, A-1-2-1-98c (1.00 g, 3.96 mmol), dicesium carbonate (2.58 g, 7.93 mmol), and compound A-7-1-1-2a (851.0 mg, 4.76 mmol) were dissolved in N,N-dimethylformamide (10 mL) in a dry 100 mL three-neck flask, and the mixture was stirred at 20 °C for 2 h. The reaction progress was monitored by LCMS. After the reaction was completed, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was used directly in the next step. A yellow oily compound A-7-1-1-2b (1.35 g, 3.68 mmol, 93.0% yield, 95.6% purity) was obtained. MS-ESI: [M+H] + =351.1 1 H NMR(400MHz,DMSO-d6)δ 7.46-7.31(m,3H),7.24(d,J=7.6Hz,1H),7.15(d,J=2.0Hz,1H),6.97-6.84(m,2H),6. 34(s,1H),6.20(s,1H),6.06(d,J=0.8Hz,1H),4.87(s,2H),3.74(s,3H),2.11(s,3H).

[0357] In step 2, compound A-7-1-1-2b (1.05 g, 3.00 mmol) was dissolved in ethyl acetate (5 mL) in a dry 100 mL three-neck flask, purged with nitrogen, and an ethyl acetate solution of water-wet palladium on carbon (0.16 g, 30.0 μmol, 10.0% purity) was added. The mixture was degassed under vacuum, purged with nitrogen multiple times, and flushed with hydrogen (15.0 Psi) and stirred at 20 °C for 12 h. The reaction progress was monitored by LCMS. After completion of the reaction, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated to give the product. The crude product was used directly in the next step. A-7-1-1-2c (0.85 g, 1.21 mmol, 40.2% yield, 50.0% purity) was obtained as a yellow oil. MS-ESI: [M+H] + =353.1

[0358] In step 3, compound A-7-1-1-2c (0.85 g, 2.41 mmol) was dissolved in tetrahydrofuran (10 mL) in a dry 100 mL three-neck flask, and concentrated hydrochloric acid (10 mL, 37% purity) was added. The mixture was stirred at 20 °C for 1 h. The reaction progress was monitored by LCMS. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative HPLC (column: Phenomene*Luna C18 250 × 50 mm × 10 μm, mobile phase: [water (hydrochloric acid)-acetonitrile], B%: %-67%, 20 min) to give compound A-7-1-1-2d (300.0 mg, 887 μmol, yield 36.8%, purity 100%) as a yellow oil. MS-ESI: [M+H] + =339.0

[0359] In step 4, compound A-7-1-1-2d (287.0 mg, 848 μmol, 1.00 equiv.), dimethylamine (42.10 mg, 933 μmol, 47.3 μL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (484.0 mg, 1.27 mmol), and N,N-diisopropylethylamine (329.0 mg, 2.54 mmol) were dissolved in N,N-dimethylformamide (1 mL) in a dry 100 mL three-neck flask, and the mixture was stirred at 20 °C for 2 h. The reaction progress was monitored by LCMS. After completion of the reaction, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (5.00 mL × 3). The combined organic phase was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by pre-HPLC (column: Phenomene*Luna C18 200 × 40 mm × 10 μm, mobile phase: [water (hydrochloric acid)-acetonitrile], B%: 40%-70%, 10 min) to obtain a yellow solid A-7-1-1-2 (207.0 mg, 543 μmol, yield 64.0%, purity 95.8%). MS-ESI: [M+H] + =366.1 1 H NMR(400MHz,DMSO-d6)δ 7.46-7.31(m,3H),7.24(d,J=7.2Hz,1H),7.08(d,J=1.6Hz,1H),6.86(t,J=1.2Hz,2H),6.18(s,1H),4.26-4.2 2(m,1H),3.99-3.96(m,1H),3.68-3.55(m,1H),3.05(s,3H),2.83(s,3H),2.10(s,3H),1.08(d,J=6.8Hz,3H).

[0360] [Production Example (3) 59: Compound A-1-2-1-42] [ka] In step 1, A-1-2-1-33c (1.00 g, 2.76 mmol) and A-1-2-1-42a (1.09 g, 2.76 mmol) were placed in a dry 50 mL three-neck flask, and the flask was purged with nitrogen. Then, tetrakis(triphenylphosphine)palladium(0) (79.7 mg, 0.05 mmol) was added and dissolved in 5 mL of dioxane. Finally, dimethyl dicarbonate (462.6 mg, 3.45 mmol) was added, and the mixture was heated at 115°C for 2 hours (preferably 10 min). The reaction was monitored for 2-4 hours, and when LCMS showed the reaction was complete, it was cooled to room temperature and filtered. The filtrate was collected, added with 10 mL of water, extracted with ethyl acetate (10 mL x 3), washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5-30%) to obtain intermediate A-1-2-1-42b (930.0 mg, 1.86 mmol, yield 67.62%). MS-ESI: [M+H] + =499.1

[0361] In step 2, A-1-2-1-42a (800.0 mg, 1.60 mmol) was added to a dry 50 mL three-neck flask and dissolved in 5 mL of tetrahydrofuran. The mixture was cooled to 0 °C, and 5 mL of 2 M aqueous sodium hydroxide was added. The mixture was allowed to react for 30 minutes (preferably 0.5 to 2 hours). When TLC showed the reaction was complete, the pH was adjusted to 1 with 1 M aqueous hydrochloric acid, extracted with ethyl acetate (5 mL x 3), washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, spin-dried, and purified via silica gel column chromatography (DCM:MeOH = 50:1) to obtain the desired product A-1-2-1-42 (237.0 mg, 0.489 mmol, 30.48% yield). MS-ESI:[MH] - =483.1 1 H NMR(400MHz,DMSO-d6)δ 8.52(dd,J=7.0,2.4Hz,1H),8.37-8.32(m,1H),7.68(dd,J=8.7,2.1Hz,1H),7.59-7.48(m,2H),7.42(dq,J=8.4,5.5,4.4 Hz,1H),7.09(dd,J=4.0,2.4Hz,1H),6.96-6.86(m,2H),6.31(s,1H),6.26(qd,J=6.7,4.0Hz,1H),1.58(d,J=6.7Hz,3H).

[0362] [Production example (3) 60: Compound A-1-10-1-20] [ka] In step 1, A-1-2-1-98c (500.0 mg, 1.38 mmol) and A-1-10-1-20a (530.0 mg, 2.48 mmol) were added to a dry 50 mL three-neck flask and purged with nitrogen. Then, tetrakis(triphenylphosphine)palladium(0) (79.70 mg, 0.07 mmol) was added and dissolved in 5 mL of dioxane. Finally, dimethyl dicarbonate (462.6 mg, 3.45 mmol) was added and the mixture was heated at 115 °C for 2 hours ( Preferably, the reaction is allowed to proceed for 2-4 hours, and the reaction is monitored. When LCMS indicates the reaction is complete, the reaction is cooled to room temperature and filtered. The filtrate is collected, 10 mL of water is added, extracted with ethyl acetate (10 mL x 3), washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 3:1) to obtain intermediate A-1-10-1-20b (590.0 mg, 1.26 mmol, yield 91.10%). MS-ESI: [M+H] + =470.0

[0363] In step 2, A-1-10-1-20b (400.0 mg, 0.85 mmol) was added to a dry 50 mL three-neck flask and dissolved in 5 mL of tetrahydrofuran. The mixture was cooled to 0 °C, and 2 mL of 2 M aqueous sodium hydroxide was added. The mixture was allowed to react for 30 minutes (preferably 0.5 to 2 hours). When TLC showed the reaction was complete, the pH was adjusted to 1 with 1 M aqueous hydrochloric acid, extracted with ethyl acetate (5 mL x 3), washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, spin-dried, and subjected to silica gel column chromatography (DCM:MeOH = 50:1). The desired product A-1-10-1-20 (102.0 mg, 0.178 mmol, 22.0% yield) was obtained by separation on a preparative plate (10% DCM:MeOH). MS-ESI:[MH] - =454.1

[0364] [Production Example (3) 61: Compound A-1-2-1-45] [ka] In step 1, A-1-2-1-45a (20.00 g, 76.65 mmol) was placed in a dry 500 mL three-neck flask and purged with nitrogen. Anhydrous tetrahydrofuran (200 mL) was then added and dissolved. The temperature was lowered to 0°C, and isopropyl magnesium chloride (2 M, 42.16 mL, 84.32 mmol) was slowly added dropwise, with the reaction temperature controlled so as not to exceed 5°C. After the entire mixture was added, the mixture was stirred for 1 hour at 0°C. N-methoxy-N-methylpropionamide (9.88 mL, 84.32 mmol) diluted with anhydrous tetrahydrofuran (30 mL) was added dropwise. After the entire mixture was added, the mixture was cooled to 25°C and allowed to react for 2 hours. When LCMS showed that the reaction was complete, the temperature was lowered to 0°C and slowly quenched with saturated NH4Cl solution, controlling the quenching temperature not to exceed 5°C. After the quenching was completed, the mixture was extracted with ethyl acetate (100 mL x 3), separated, and the organic phases were combined, washed with saturated sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain intermediate A-1-2-1-45b (18.70 g, 70.69 mmol, yield 85.0%). MS-ESI: [M+H] + =237.9 1 H NMR (400 MHz, chloroform-d) δ 8.29 (t, J = 1.7 Hz, 1H), 8.15 (d, J = 1.7 Hz, 1H), 7.96 (t, J = 1.7 Hz, 1H), 3.10-2.89 (m, 2H), 1.24 (td, J = 7.2, 1.6 Hz, 3H).

[0365] In step 2, palladium acetate (0.48 g, 2.12 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.23 g, 2.12 mmol) were added to a dry 500 mL three-neck flask and the flask was flushed with nitrogen. Next, A-1-2-1-45b (18.70 g, 70.69 mmol) and dicyclohexylcarbodiimide (2.92 g, 14.14 mmol) were added to the flask, and N,N-dimethylformamide (200 mL) was added to dissolve the mixture. The atmosphere was again thoroughly flushed with nitrogen. Next, formic acid (18.67 mL, 494.83 mmol) and triethylamine (19.65 mL, 141.38 mmol) were slowly added to the flask in this order, and the temperature was raised to 80°C (preferably 80 to 100°C) and the mixture was stirred for 4 hours (preferably 4 to 8 hours). LCMS showed that the reaction was complete. The reaction mixture was cooled to room temperature and quenched by adding water (200 mL). The reaction mixture was filtered through diatomaceous earth to remove insoluble matter, and then extracted with tert-butyl methyl ether (150 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (DCM:MeOH = 15:1) to give intermediate A-1-2-1-45c (9.50 g, 46.75 mmol, yield 59.5%). MS-ESI:[MH] - =202.1 1 H NMR(400MHz,DMSO-d6)δ 8.63(d,J=5.0Hz,2H),8.51(s,1H),3.15(q,J=7.0Hz,2H),1.10(t,J=7.1Hz,3H).

[0366] In step 3, A-1-2-1-45c (9.50 g, 46.75 mmol) was placed in a dry 100 mL three-neck flask, purged with nitrogen, and dissolved in 20 mL of 3.3 M potassium hydroxide solution and 30 mL of methanol. The temperature was raised to 80 °C (preferably 60-80 °C) and stirred for 2 hours (preferably 2-4 hours). LCMS showed the reaction was complete. The mixture was cooled to room temperature, filtered, and the filtrate was collected. The pH of the filtrate was adjusted to 1 with 2 M hydrochloric acid solution, extracted with ethyl acetate (50 mL x 3), and the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (DCM:MeOH = 15:1, 1:1000 AcOH) to give intermediate A-1-2-1-45d (4.30 g, 19.35 mmol, 48.47% yield). MS-ESI:[MH] - =221.1 1 H NMR(400MHz,DMSO-d6)δ 8.75-8.61(m,3H),5.01(t,J=6.5Hz,2H),1.32(t,J=6.2Hz,3H).

[0367] In st...

Claims

1. A benzopyrone compound represented by formula (I), or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated product thereof, or a hydrate thereof, or a solvate thereof, 【Chemistry 1】 In the formula, X １ and X ２ are each independently selected from an O or NH group, and Y is selected from a CR group or N, where R is H or C １ ~C ３ is an alkyl group, and R １ and R １ ' may be the same or different and are each independently selected from hydrogen, an alkyl group, a cycloalkyl group, an aryl group, a heterocyclyl group, or a heteroaryl group; L １ and L ３ are -O-, -S-, and -NR, respectively. ３ -, -CR ２ R ３ -, -CR ２ (R ３ ), —CO—, —SO— or —SO ２ - groups, and L ２ is a direct bond, -CR ２ R ３ -, -CR ２ (R ３ ) - or -C(R ２ R ３ )—, where R ２ is H or C １ ~C ４ A chain alkyl group is selected from R ３ is H or C １ ~C ４ A group selected from a chain alkyl group or a group of -CR ２ (R ３ ) in R ２ and R ３ together form one oxyylidene, R ４ , R ５ and R ６ are H, halogen, and —C—OR ８ (R ９ ), -CR ８ (R ９ ), -CN, -NO ２ , -OR ８ , -NR ８ R ９ , -SR ８ , -COR ８ , -SOR ８ , -SO ２ R ８ , -NR ８ COR ９ , -CONR ８ R ９ , -OCOR ８ , -COOR ８ , -OCONR ８ R ９ , -NR ８ CONR ９ R １０ , -NR ８ COOR ９ , -NR ８ SO ２ R ９ , -SO ２ NR ８ R ９ , -OSO ２ R ８ , -SO ３ R ８ , an open-chain alkyl group, a hetero-open-chain alkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkene group, an alkyne group, an aryl group or a heteroaryl group, or an aromatic fused heterocyclyl group, wherein R ８ , R ９ , R １０ are each independently selected from H, a linear alkyl group, a heterocyclic alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, wherein the linear alkyl group, the heterocyclic alkyl group, the cycloalkyl group, the heterocycloalkyl group, the aryl group, or the heteroaryl group is independently selected from one or more R １１ and R １１ is selected from halogen, cyano group, hydroxy group, mercapto group, ether group, nitro group, alkoxy group, amino group, amine group, carboxy group, sulfonic acid group, ester group, acyloxy group, amide group, sulfonate ester group, sulfonamide group, linear alkyl group, heterocyclic alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group, or aromatic fused heterocyclyl group, wherein each linear alkyl group, heterocyclic alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group, or aromatic fused heterocyclyl group is independently optionally substituted by one or more halogen, cyano group, hydroxy group, mercapto group, ether group, nitro group, alkoxy group, amino group, amine group, carboxy group, sulfonic acid group, ester group, amide group, sulfonate ester group, sulfonamide group, alkyl group, or haloalkyl group, or R ４ , R ５ together form one oxyylidene, Or, R ４ , R ５ and R ６ Any two or three of the ３ Together with the carbon atom bonded to L ３ A cyclic group bonded to 【Chemistry 2】 wherein the cyclic group A is an arylcyclyl group, a saturated or unsaturated cycloalkyl group, a monoheterocyclyl group, a fused heterocyclyl group, a benzoheterocyclyl group, a spirocyclic group, a bridged ring group, and the like. １１ any one cyclic group is selected from cyclic groups substituted by W is hydrogen, H, an alkyl group, or —CR ８ａ R ９ａ R １０ａ , -NR ８ａ R ９ａ , -OR １０ａ , or one or more R ７ a cyclic group B1 containing a carbon atom and attached to the benzopyrone ring by said carbon atom, 【Transformation 3】 or a cyclic group B2 containing a nitrogen atom and bonded to the benzopyrone ring by the nitrogen atom 【Chemistry 4】 where R ８ａ , R ９ａ and R １０ａ are each independently selected from H, halogen, an alkyl group, a cyano group, a hydroxy group, a mercapto group, an ether group, a nitro group, an alkoxy group, an amino group, an amine group, a carboxy group, a sulfonic acid group, an ester group, an acyloxy group, an amide group, a sulfonate ester group, a sulfonamide group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an aromatic fused heterocyclyl group; the cyclic group B1 and the cyclic group B2 are each independently selected from a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; Here, R ７ is H, halogen, -CN, -NO ２ , -OR ８ , -NR ８ R ９ , -SR ８ , -COR ８ , -SOR ８ , -SO ２ R ８ , -NR ８ COR ９ , -CONR ８ R ９ , -OCOR ８ , -COOR ８ , -OCONR ８ R ９ , -NR ８ CONR ９ R １０ , -NR ８ COOR ９ , -NR ８ SO ２ R ９ , -SO ２ NR ８ R ９ , -OSO ２ R ８ , -SO ３ R ８ , a chain alkyl group, a heterochain alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or heteroaryl group, or an aromatic fused heterocyclyl group, and preferably selected from a halogen, an alkyl group, a cyano group, a hydroxy group, a mercapto group, an ether group, a nitro group, an alkoxy group, an amino group, an amine group, a carboxy group, a sulfonic acid group, an ester group, an amide group, an acyloxy group, a sulfonate ester group, a sulfonamide group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, wherein each chain alkyl group, heterochain alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group, or aromatic fused heterocyclyl group independently represents one or more R １１ and R ８ , R ９ and R １０ The meaning of is R ４ , R ５ and R ６ R appears in ８ , R ９ and R １０ is exactly the same as the meaning of However, the formula (I) includes the following compounds: 【Transformation 5】 or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated product thereof, or a hydrate thereof, or a solvate thereof, which does not include:

2. The X １ is an —O— group, and X ２ is an —O— group, Y is a —CR— group, and R １ and R １ ' are both hydrogen, Or X １ is an —NH— group, and X ２ is an —O— group, Y is a —CR— group, and R １ and R １ ' are both hydrogen, Or X １ is an —O— group, and X ２ is a —NH— group, Y is a —CR— group, and R １ and R １ ' are both hydrogen, Or X １ is an —O— group, and X ２ is an —O— group, Y is an —N— group, and R １ and R １ 2. The compound of claim 1, wherein both ' and ' are hydrogen, or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated product thereof, or a hydrate thereof, or a solvate thereof.

3. Said-L １ -L ２ -L ３ - is, as a whole, -O-CR ２ (R ３ ) -CO-, -O-CR ２ R ３ -CO-, -CR ２ (R ３ )-CR ２ (R ３ ) —CO—, —NR ３ -CR ２ (R ３ ) -CO-, -S-CR ２ (R ３ ) —CO—, —SO ２ -CR ２ (R ３ ) -CO-, -O-CR ２ (R ３ )-CR ２ R ３ -, -O-CR ２ (R ３ )-SO ２ - and - CR ２ (R ３ )-NR ３ any one group selected from the group consisting of —CO—; Here, the R ２ is preferably one of H, a methyl group, and an ethyl group, more preferably a methyl group, and R ３ is preferably a methyl group or H, more preferably H. The compound according to claim 1 or 2, or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated product thereof, or a hydrate thereof, or a solvate thereof.

4. Said-L １ -L ２ -L ３ - as a whole is -O-CH(CH ３ ) -CO-, -O-CR ２ (R ３ ) —CO—, —CR ２ R ３ -CH(CH ３ ) —CO—, —NR ３ -CH(CH ３ )-CO-, -S-CH(CH ３ ) —CO—, —SO ２ -CH(CH ３ ) -CO-, -O-CR ２ (R ３ )-CR ２ (R ３ ) - and -O-CH(CH ３ )-SO ２ -or-CR ２ (R ３ )-NR ３ The compound according to any one of claims 1 to 3, or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated product thereof, or a hydrate thereof, or a solvate thereof, wherein any one group is selected from the group consisting of -CO-.

5. The cyclic group A is C ３ ~C １２ Cycloalkyl group, C ３ ~C １２ Heterocycloalkyl group, C ５ ~C １２ Aryl groups and C ５ ~C １２ Any one cyclic group is selected from heteroaryl groups, and preferably C ３ ~C １２ selected from a cycloalkyl group, a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group, an anthraquinone group, a furyl group, a pyrrolyl group, a thienyl group, a pyrazolyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, an isothiazolyl group, a pyridyl group, a pyranyl group, a thiopyranyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a piperazinyl group, an indolyl group, a benzimidazolyl group, a carbazolyl group, a thiazolinyl group, a quinolinyl group, an isoquinolinyl group, a purinyl group, an acridinyl group, a phenazinyl group, and a phenothiazinyl group; More preferably, the cyclic group A is any one selected from the following cyclic groups: 【Transformation 6】 wherein these cyclic groups A may be substituted with one or more groups selected from halogen, cyano group, hydroxy group, mercapto group, ether group, nitro group, alkoxy group, amino group, amine group, carboxy group, sulfonic acid group, ester group, amide group, sulfonate ester group, sulfonamide group, linear alkyl group, linear heteroalkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group; or a stereoisomer, salt, prodrug, deuterated product, hydrate, or solvate of the compound according to any one of claims 1 to 4.

6. The R ４ , R ５ and R ６ are respectively, -CR ８ (R ９ ) are independently selected from R ８ is H, a chain alkyl group, a cyano group, or a cycloalkyl group, and R ９ is a chain alkyl group, a heterochain alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group substituted with a halogen, a cyano group, a hydroxy group, a mercapto group, an ether group, a nitro group, an alkoxy group, an amino group, an amine group, a carboxy group, a sulfonic acid group, an ester group, an acyl group, an amide group, a sulfonate ester group, or a sulfonamide group, R ９ is connected to L by an oxygen atom, a nitrogen atom, or a carbon atom on the substituent. ３ The compound according to any one of claims 1 to 5, wherein the compound is bonded to a carbon atom bonded to

7. the substituted cyclic group B1 and the substituted cyclic group B2 are each independently selected from a halocycloalkyl group, a haloheterocycloalkyl group, a haloaryl group, and a haloheteroaryl group; More preferably, the substituted cyclic group B1 and the substituted cyclic group B2 are each independently a 2-chloro-4-fluorophenyl group, a chlorophenyl group, a methyl-substituted phenyl group, an amido-substituted phenyl group, an amino-substituted phenyl group, or a phenylalkyl group.

8. The cyclic group B1 is C ５ ~C １０ Aryl group, C ５ ~C １０ Heteroaryl group, C ３ ~C １０ Cycloalkyl group or C ３ ~C １０ The compound according to any one of claims 1 to 7, which is a heterocycloalkyl group, or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated product thereof, or a hydrate thereof, or a solvate thereof.

9. The compound of formula (I) is selected from compounds represented by any one of the following structural formulas: 【Transformation 7】 In the formula, R ７ is preferably F, Cl, Br, I, OH, OR ２ , C １～３ R is one or more of an alkyl group, a sulfonic acid group, a nitro group, an amino group, and an amine group; １ and R １ ' is hydrogen, C １～４ Alkyl group, C １～４ alkoxy groups, where R ２ is the same as defined in claim 1, and n is an integer of 0 to 5, 【Transformation 8】 In the formula, R ７ is preferably F, Cl, Br, I, OH, OR ２ａ , C １～３ R is one or more of an alkyl group, a sulfonic acid group, a nitro group, an amino group, or an amine group; １１ is preferably F, Cl, Br, I, C １～４ an alkoxy group, an acyl group, or C １～３ Alkyl group, sulfonic acid group, nitro group, amino group, cyano group, amine group, -C ０～４ Alkyl-COOH, ester group, acyloxy group, ether group, amide group, amine acyl group, cycloalkyl-substituted amine acyl group, aralkyl-substituted amine acyl group, carboxy-substituted C １～３ Alkoxy group, carboxy-substituted amine group, cycloalkyl-substituted C １～３ C containing alkoxy group and acyloxy group ３～５ a cycloalkyl group, or 【Chemistry 9】 wherein R １１ may form a benzene-fused nitrogen heterocyclic or oxygen heterocyclic structure with the benzene ring bonded thereto, and R １ and R １ ' is hydrogen, C １～４ Alkyl group, C １～４ alkyloxy groups, R ２ａ is C １ ~C ４ Alkyl group, C １ ~C ４ Alkenyl group, C １ ~C ２ Alkoxy-substituted C １ ~C ４ Alkyl group, C １ ~C ４ alkyl-substituted formyl groups, n is an integer from 0 to 5; 【Chemistry 10】 In the formula, R １１ is preferably -C ０～４ alkyl-COOH, and R １ and R １ ' is hydrogen, C １～４ Alkyl group, C １～４ Alkoxy group, C １～４ independently selected from alkylphenyl groups; 【Chemistry 11】 During the ceremony, 【Chemistry 12】 is preferably C １～４ Alkyl group, C １～４ is an alkylphenyl group, more preferably a methyl group, an isobutyl group, or a benzyl group; R １１ is preferably -C ０～４ alkyl-COOH, and R １ and R １ ' is hydrogen, C １～４ Alkyl group, C １～４ Alkoxy group, C １～４ independently selected from alkylphenyl groups; 【Chemistry 13】 In the formula, R １０ is preferably C １～４ Alkyl group, hydroxy-substituted C １～４ Alkyl group, C １～４ Alkoxy or hydroxy-substituted C １～４ is an alkoxy group, and R １１ is preferably -C ０ ~C ４ alkyl-COOH, and R １ and R １ ' is hydrogen, C １～４ Alkyl group, C １～４ Alkoxy group, C １～４ independently selected from alkylphenyl groups; 【Chemistry 14】 In the formula, R ８ and R ９ is hydrogen or C １～４ alkyl groups, R １１ is preferably -C ０ ~C ４ alkyl-COOH, and R １ and R １ ' is hydrogen, C １～４ Alkyl group, C １～４ Alkoxy group, C １～４ independently selected from alkylphenyl groups; 【Chemistry 15】 In the formula, the cyclic group B1 is preferably C ３～１２ a cycloalkyl group, a 4- to 10-membered heterocyclyl group, or a 5- to 10-membered aryl group; R １１ is preferably -C ０ ~C ４ alkyl-COOH, and the heterocyclyl group is more preferably any one of a furyl group, a pyrrolyl group, a thienyl group, a pyrazolyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, an isothiazolyl group, a pyridyl group, a pyranyl group, a thiopyranyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a piperazinyl group, an indolyl group, a benzimidazolyl group, a carbazolyl group, a thiazolinyl group, a quinolinyl group, an isoquinolinyl group, a purinyl group, an acridinyl group, a phenazinyl group, and a phenothiazinyl group; １ and R １ ' are both preferably hydrogen, C １～４ Alkyl group, C １～４ Alkoxy group, C １～４ The cyclic group B1 is an alkylphenyl group, and the cyclic group B1 may optionally contain one or more hydrogen, halogen, hydroxyl, C １～６ Alkyl group, C １～６ substituted or unsubstituted with hydroxy groups, amino groups, amine groups substituted with alkyl groups, 【Chemistry 16】 In the formula, the cyclic group B2 is preferably C ３～１２ a cycloalkyl group, a 4- to 10-membered heterocyclyl group, or a 5- to 10-membered aryl group; R １１ is preferably -C ０～４ The heterocyclyl group is more preferably any one of a furyl group, a pyrrolyl group, a thienyl group, a pyrazolyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, an isothiazolyl group, a pyridyl group, a pyranyl group, a thiopyranyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a piperazinyl group, an indolyl group, a benzimidazolyl group, a carbazolyl group, a thiazolinyl group, a quinolinyl group, an isoquinolinyl group, a purinyl group, an acridinyl group, a phenazinyl group, and a phenothiazinyl group; R １ and R １ ' are preferably both hydrogen, and the cyclic group B2 is hydrogen, halogen, a hydroxy group, C １～６ Alkyl group, C １～６ substituted with one or more groups arbitrarily selected from a hydroxy group, an amino group, and an amine group substituted with an alkyl group, or not substituted; 【Chemistry 17】 In the formula, R ７ is preferably F, Cl, Br, I, OH, C １～６ It is one or more of an alkyl group, a sulfonic acid group, a nitro group, an amino group, and an amine group, and more preferably, chlorine and fluorine simultaneously substitute the benzene ring in the structural formula, and R １１ is preferably F, Cl, Br, I, oxo, C １～３ Alkoxy group or alkyl group, cycloalkyl group, sulfonic acid group, nitro group, amino group, cyano group, amine group, -C ０～４ R is one or more groups selected from the group consisting of an alkyl-carboxy group, an ester group, an acyloxy group, and an ether group. １ and R １ ' is hydrogen, C １～４ Alkyl group, C １～４ Alkoxy group, C １～４ alkylphenyl groups, n is an integer from 0 to 5, and R ２ａ is C １ ~C ４ Alkyl group, C １ ~C ４ Alkenyl group, C １ ~C ２ Alkoxy-substituted C １ ~C ４ Alkyl group, C １ ~C ４ alkyl-substituted formyl groups; [Chemistry 18] The R ７ is preferably F, Cl, Br, I, OH, OR ２ａ , C １～６ R is any one or more of an alkyl group, a sulfonic acid group, a nitro group, an amino group, and an amine group, and more preferably, chlorine and fluorine simultaneously substitute the benzene ring in the structural formula, and R １１ is preferably F, Cl, Br, I, oxo, C １～６ Alkoxy group, C １～６ an alkyl group, a cycloalkyl group, a sulfonic acid group, a nitro group, an amino group, a cyano group, an amine group, or -C ０～４ alkyl-carboxy groups, and R １ and R １ ' is hydrogen, C １～４ Alkyl group, C １～４ Alkoxy group, C １～４ alkylphenyl groups, n is an integer from 0 to 5, and R ２ａ is C １ ~C ４ Alkyl group, C １ ~C ４ Alkenyl group, C １ ~C ２ Alkoxy-substituted C １ ~C ４ Alkyl group, C １ ~C ４ alkyl-substituted formyl groups; 【Chemistry 19】 In the formula, R ７ is preferably F, Cl, Br, I, OH, OR ２ａ , C １～６ R is any one or more of an alkyl group, a sulfonic acid group, a nitro group, an amino group, and an amine group, and more preferably, chlorine and fluorine simultaneously substitute the benzene ring in the structural formula, and R １１ is preferably F, Cl, Br, I, oxo, C １～６ Alkoxy group, C １～６ Alkyl group, C ３～１０ Cycloalkyl group, sulfonic acid group, hydroxy group, hydroxy-substituted C １～６ an alkyl group, a nitro group, an amino group, a cyano group, an amine group, or —C ０～４ alkylcarboxy groups, n is an integer of 0 to 5, and R ２ａ is C １ ~C ４ Alkyl group, C １ ~C ４ Alkenyl group, C １ ~C ２ Alkoxy-substituted C １ ~C ４ Alkyl group, C １ ~C ４ alkyl-substituted formyl groups; 【Chemistry 20】 In the formula, R ７ is preferably F, Cl, Br, I, OH, OR ２ａ , C １～６ Alkyl group, C ３～１０ R is any one or more of a cycloalkyl group, a sulfonic acid group, a nitro group, an amino group, and an amine group, and more preferably, chlorine and fluorine simultaneously substitute the benzene ring in the structural formula, and R １１ is preferably F, Cl, Br, I, oxo, C １～３ Alkoxy group or alkyl group, cycloalkyl group, sulfonic acid group, hydroxy group, nitro group, amino group, cyano group, amine group, -C ０～４ alkylcarboxy groups, n is an integer of 0 to 5, and R ２ａ is C １ ~C ４ Alkyl group, C １ ~C ４ Alkenyl group, C １ ~C ２ Alkoxy-substituted C １ ~C ４ Alkyl group, C １ ~C ４ alkyl-substituted formyl groups; 【Chemistry 21】 In the formula, R ７ is preferably F, Cl, Br, I, OH, OR ２ａ or C １～３ It is one or more of an alkyl group, a sulfonic acid group, a nitro group, an amino group, and an amine group, and more preferably, chlorine and fluorine simultaneously substitute the benzene ring in the structural formula, and R １１ may be hydrogen, F, Cl, Br, I, oxo, C １～６ Alkoxy group, C １～６ Alkyl group, C ３～１０ Cycloalkyl group, sulfonic acid group, hydroxy group, nitro group, amino group, cyano group, amine group, -C ０～４ alkylcarboxy groups, n is an integer of 0 to 5, and R ２ａ is C １ ~C ４ Alkyl group, C １ ~C ４ Alkenyl group, C １ ~C ２ Alkoxy-substituted C １ ~C ４ Alkyl group, C １ ~C ４ alkyl-substituted formyl groups; 【Chemistry 22】 In the formula, the cyclic group A is a halogen, a cyano group, a hydroxy group, a mercapto group, an ether group, a nitro group, an alkoxy group, an amino group, an amine group, -C ０～４ an aryl group, a cycloalkyl group, a heterocycloalkyl group, or a heteroaryl group, which may or may not be substituted by one or more groups selected from an alkyl-carboxy group, a sulfonic acid group, an ester group, an amide group, a sulfonate ester group, a sulfonamide group, a chain alkyl group, a heterochain alkyl group, a cycloalkyl group, and a heterocycloalkyl group, wherein the cycloalkyl group is preferably C ３～６ The heterocycloalkyl group is preferably any one of an oxiranyl group, an oxetanyl group, an aziridinyl group, an azetidinyl group, and a thietanyl group, and the heteroaryl group is preferably a furyl group, a thienyl group, a pyrrolyl group, an oxazolyl group, a thiazolyl group, an imidazolyl group, a pyrazolyl group, a 5-membered heteroaryl group such as an oxygen-containing imidazolyl group or a pyrazolyl group, a pyridyl group, a pyrimidinyl group, a pyranyl group, a pyridazinyi group, a pyridazinyl ... benzoheterocyclyl groups such as benzoyl, pyrazinyl, pyrone-formed or pyranyl groups; benzofuryl, benzothienyl, benzopyrrolyl, indolyl, quinolinyl, isoquinolinyl, benzopyranyl, benzo-γ-pyrone-formed or benzo-γ-pyrone-formed heterocyclyl groups; heterocyclic-fused heterocyclyl groups such as purinyl groups; W is preferably a 2-chloro-4-fluoro-substituted phenyl group or a 2-methylphenyl group; R １ and R １ ' is hydrogen, C １～４ Alkyl group, C １～４ Alkoxy group, C １～４ independently selected from alkylphenyl groups; 【Chemistry 23】 wherein the cyclic group A is preferably a fused ring or aromatic fused heterocyclyl group, more preferably a benzoheterocyclyl group such as a benzofuryl group, a benzothienyl group, a benzopyrrolyl group, an indolyl group, a quinolinyl group, an isoquinolinyl group, a benzopyranyl group, or a group formed by benzo-γ-pyrone, W is preferably a 2-chloro-4-fluoro-substituted phenyl group or a 2-methylphenyl group, and R １ and R １ ' is hydrogen, C １～４ Alkyl group, C １～４ Alkoxy group, C １～４ independently selected from alkylphenyl groups; 【Chemistry 24】 wherein the cyclic group A is preferably selected from spirocyclic or bridged ring groups, W is preferably a 2-chloro-4-fluorosubstituted benzene or 2-methylphenyl group, and R １ and R １ ' is hydrogen, C １～４ Alkyl group, C １～４ Alkoxy group, C １～４ independently selected from alkylphenyl groups; 【Chemistry 25】 In the formula, the cyclic group A is preferably a phenyl group, a halophenyl group, -C ０～４ is preferably a 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl group; R １ and R １ ' is hydrogen, C １～４ Alkyl group, C １～４ Alkoxy group, C １～４ independently selected from alkylphenyl groups; 【Chemistry 26】 wherein the cyclic group A is preferably R １１ as F, Cl, Br, I, oxo, C １～６ Alkoxy group, C １～６ Alkyl group, C ３～１０ a cycloalkyl group, a sulfonic acid group, a nitro group, an amino group, a cyano group, an amine group, or -C ０～４ The cyclic group A is preferably a phenyl group substituted or unsubstituted by one or more groups selected from the group consisting of alkyl-carboxy groups, and R １１ W is preferably a 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl group, and R １ and R １ ' is hydrogen, C １～４ Alkyl group, C １～４ Alkoxy group, C １～４ independently selected from alkylphenyl groups; 【Chemistry 27】 wherein the cyclic group A is preferably R １１ as F, Cl, Br, I, oxo, C １～６ Alkoxy group, C １～６ Alkyl group, C ３～１０ a cycloalkyl group, a sulfonic acid group, a nitro group, an amino group, a cyano group, an amine group, or -C ０～４ The cyclic group A is preferably a phenyl group substituted or unsubstituted by one or more groups selected from the group consisting of alkyl-carboxy groups, and R １１ W is preferably a 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl group, and R １ and R １ ' is hydrogen, C １～４ Alkyl group, C １～４ Alkoxy group, C １～４ independently selected from alkylphenyl groups; 【Chemistry 28】 wherein the cyclic group A is preferably R １１ as F, Cl, Br, I, oxo, C １～６ Alkoxy group, C １～６ Alkyl group, C ３～１０ a cycloalkyl group, a sulfonic acid group, a nitro group, an amino group, a cyano group, an amine group, or -C ０～４ The cyclic group A is preferably a phenyl group substituted or unsubstituted by one or more groups selected from the group consisting of alkyl-carboxy groups, and R １１ W is preferably a 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl group, and R １ and R １ ' is hydrogen, C １～４ Alkyl group, C １～４ Alkoxy group, C １～４ independently selected from alkylphenyl groups; 【Chemistry 29】 wherein the cyclic group A is preferably R １１ as F, Cl, Br, I, oxo, C １～６ Alkoxy group, C １～６ Alkyl group, C ３～１０ a cycloalkyl group, a sulfonic acid group, a nitro group, an amino group, a cyano group, an amine group, or -C ０～４ The cyclic group A is preferably a phenyl group substituted or unsubstituted by one or more of R alkylcarboxy groups as a carboxy group. １１ and W is preferably a 2-chloro-4-fluoro-substituted benzene, and R １ and R １ ' is hydrogen, C １～４ Alkyl group, C １～４ Alkoxy group, C １～４ independently selected from alkylphenyl groups; 【Transformation 30】 In the formula, R ７ is hydrogen, C １～４ Alkyl group, C １～４ alkoxy groups, n is an integer from 0 to 5, and R ２ , R ３ is hydrogen, C １～４ alkyl groups, R ４ , R ５ together form one oxyylidene, 【Chemistry 31】 In the formula, R ２ and R ３ are each independently preferably hydrogen, C １～６ alkyl group, or a set of R ２ , R ３ together form an oxyylidene, and another pair of R ２ , R ３ are independently preferably hydrogen, C １～６ is an alkyl group, and R １ and R １ ' is hydrogen, C １～４ Alkyl group, C １～４ Alkoxy group, C １～４ independently selected from alkylphenyl groups; 【Chemistry 32】 In the formula, the cyclic group A is preferably F, Cl, Br, I, oxo, C １～６ Alkoxy group, C １～６ Alkyl group, C ３～１０ is a phenyl group which may be unsubstituted or substituted with one or more of a cycloalkyl group, a sulfonic acid group, a nitro group, an amino group, a cyano group, an amine group, or a carboxy group, and the cyclic group A is preferably R as a carboxy group. １１ W is preferably a 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl group, and R １ and R １ ' are both preferably hydrogen, 【Transformation 33】 wherein the cyclic group A is preferably R １１ as F, Cl, Br, I, oxo, C １～６ Alkoxy group, C １～６ Alkyl group, C ３～１０ a cycloalkyl group, a sulfonic acid group, a nitro group, an amino group, a cyano group, an amine group, or C ０～４ The cyclic group A is preferably a phenyl group substituted with one or more of the following groups: R １１ W is preferably a 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl group, and R １ and R １ ' is hydrogen, C １～４ Alkyl group, C １～４ Alkoxy group, C １～４ independently selected from alkylphenyl groups; 【Transformation 34】 The cyclic group A is preferably F, Cl, Br, I, oxo, C １～６ Alkoxy group, C １～６ Alkyl group, C ３～１０ a cycloalkyl group, a sulfonic acid group, a nitro group, an amino group, a cyano group, an amine group, or C ０～４ The cyclic group A is preferably a phenyl group substituted or unsubstituted by one or more of R alkylcarboxy groups as a carboxy group. １１ W is preferably a 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl group, and R １ and R １ ' is hydrogen, C １～４ Alkyl group, C １～４ Alkoxy group, C １～４ independently selected from alkylphenyl groups; 【Chemistry 35】 In the formula, the cyclic group A is preferably F, Cl, Br, I, oxo, C １～６ Alkoxy group, C １～６ Alkyl group, C ３～１０ a cycloalkyl group, a sulfonic acid group, a nitro group, an amino group, a cyano group, an amine group, or C ０～４ The cyclic group A is preferably a phenyl group substituted with one or more of the following groups: R １１ W is preferably a 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl group, and R １ and R １ ' is hydrogen, C １～４ Alkyl group, C １～４ Alkoxy group, C １～４ independently selected from alkylphenyl groups; and 【Transformation 36】 In the formula, the cyclic group A is preferably F, Cl, Br, I, oxo, C １～６ Alkoxy group, C １～６ Alkyl group, C ３～１０ a cycloalkyl group, a sulfonic acid group, a nitro group, an amino group, a cyano group, an amine group, or C ０～４ The cyclic group A is preferably a phenyl group substituted with one or more of the following groups: R １１ W is preferably a 2-chloro-4-fluoro-substituted benzene or 2-methylphenyl group, and R １ and R １ ' is hydrogen, C １～４ Alkyl group, C １～４ Alkoxy group, C １～４ The compound according to any one of claims 1 to 8, or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated product thereof, or a hydrate thereof, or a solvate thereof, wherein each of the groups is independently selected from alkylphenyl groups.

10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9, or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated form thereof, or a hydrate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

11. Use of the compound according to any one of claims 1 to 9, or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated product thereof, or a hydrate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 10, in the manufacture of a drug used as a POLRMT inhibitor.

12. Use of the compound according to any one of claims 1 to 9, or a stereoisomer thereof, or a salt thereof, or a prodrug thereof, or a deuterated product thereof, or a hydrate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 3, in the manufacture of a drug for a disease associated with abnormally high expression of POLRMT due to oxidative phosphorylation.

13. 13. The use according to claim 12, wherein the disease is cancer, preferably the cancer is melanoma, metastatic melanoma, pancreatic cancer, pancreatic ductal adenocarcinoma, prostate cancer, lung cancer, hepatocellular carcinoma, lymphoma, leukemia, multiple myeloma, breast cancer, glioma, glioblastoma, cervical cancer, renal cancer, colorectal cancer or ovarian cancer.

Images